Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development
Abstract
:1. Introduction
2. Tfh Differentiation
3. T-Cell Dependent Antibody Responses
4. Memory and Circulating Tfh Cells
5. Regulation of GC Tfh Responses
6. Tfh Cells during HIV Infection and Correlates with bNAb Development
7. Induction of Tfh Responses during Immunization
7.1. Use of Adjuvants to Direct Tfh Formation
7.2. Route of Vaccine Administration
7.3. Enhanced or Extended Administration of Antigen to Induce and Maintain Tfh
8. Inhibiting Negative Regulators of GC Responses
9. Future Directions
10. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Amanna, I.J.; Slifka, M.K. Contributions of humoral and cellular immunity to vaccine-induced protection in humans. Virology 2011, 411, 206–215. [Google Scholar] [CrossRef] [PubMed]
- Fauci, A.S. An HIV Vaccine Is Essential for Ending the HIV/AIDS Pandemic. JAMA 2017, 318, 1535–1536. [Google Scholar] [CrossRef] [PubMed]
- Moldt, B.; Rakasz, E.G.; Schultz, N.; Chan-Hui, P.Y.; Swiderek, K.; Weisgrau, K.L.; Piaskowski, S.M.; Bergman, Z.; Watkins, D.I.; Poignard, P.; et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 2012, 109, 18921–18925. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gautam, R.; Nishimura, Y.; Pegu, A.; Nason, M.C.; Klein, F.; Gazumyan, A.; Golijanin, J.; Buckler-White, A.; Sadjadpour, R.; Wang, K.; et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 2016, 533, 105–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Julg, B.; Liu, P.-T.; Wagh, K.; Fischer, W.M.; Abbink, P.; Mercado, N.B.; Whitney, J.B.; Nkolola, J.P.; McMahan, K.; Tartaglia, L.J.; et al. Protection Against a Mixed SHIV Challenge by a Broadly Neutralizing Antibody Cocktail. Sci. Transl. Med. 2017, 9, eaao4235. [Google Scholar] [CrossRef] [PubMed]
- Pollara, J.; Easterhoff, D.; Fouda, G.G. Lessons Learned from Human HIV Vaccine Trials. Curr. Opin. HIV AIDS 2017, 12, 216–221. [Google Scholar] [CrossRef] [PubMed]
- Crotty, S. T Follicular Helper Cell Differentiation, Function, and Roles in Disease. Immunity 2014, 41, 529–542. [Google Scholar] [CrossRef] [PubMed]
- Landais, E.; Huang, X.; Havenar-Daughton, C.; Murrell, B.; Price, M.A.; Wickramasinghe, L.; Ramos, A.; Bian, C.B.; Simek, M.; Allen, S.; et al. Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort. PLoS Pathog. 2016, 12, e1005369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bonsignori, M.; Zhou, T.; Sheng, Z.; Chen, L.; Gao, F.; Joyce, M.G.; Ozorowski, G.; Chuang, G.Y.; Schramm, C.A.; Wiehe, K.; et al. Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. Cell 2016, 165, 449–463. [Google Scholar] [CrossRef] [PubMed]
- Breitfeld, D.; Ohl, L.; Kremmer, E.; Ellwart, J.; Sallusto, F.; Lipp, M.; Förster, R. Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production. J. Exp. Med. 2000, 192, 1545–1552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schaerli, P.; Willimann, K.; Lang, A.B.; Lipp, M.; Loetscher, P.; Moser, B. Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function. J. Exp. Med. 2000, 192, 1553–1562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Choi, Y.S.; Gullicksrud, J.A.; Xing, S.; Zeng, Z.; Shan, Q.; Li, F.; Love, P.E.; Peng, W.; Xue, H.H.; Crotty, S. LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol. 2015, 16, 980–990. [Google Scholar] [CrossRef] [PubMed]
- Xu, L.; Cao, Y.; Xie, Z.; Huang, Q.; Bai, Q.; Yang, X.; He, R.; Hao, Y.; Wang, H.; Zhao, T.; et al. The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection. Nat. Immunol. 2015, 16, 991–999. [Google Scholar] [CrossRef] [PubMed]
- Johnston, R.J.; Poholek, A.C.; DiToro, D.; Yusuf, I.; Eto, D.; Barnett, B.; Dent, A.L.; Craft, J.; Crotty, S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009, 325, 1006–1010. [Google Scholar] [CrossRef] [PubMed]
- Nurieva, R.I.; Chung, Y.; Martinez, G.J.; Yang, X.O.; Tanaka, S.; Matskevitch, T.D.; Wang, Y.H.; Dong, C. Bcl6 mediates the development of T follicular helper cells. Science 2009, 325, 1001–1005. [Google Scholar] [CrossRef] [PubMed]
- Yu, D.; Rao, S.; Tsai, L.M.; Lee, S.K.; He, Y.; Sutcliffe, E.L.; Srivastava, M.; Linterman, M.; Zheng, L.; Simpson, N.; et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009, 31, 457–468. [Google Scholar] [CrossRef] [PubMed]
- Kroenke, M.A.; Eto, D.; Locci, M.; Cho, M.; Davidson, T.; Haddad, E.K.; Crotty, S. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunol. 2012, 188, 3734–3744. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Chen, X.; Zhong, B.; Wang, A.; Wang, X.; Chu, F.; Nurieva, R.I.; Yan, X.; Chen, P.; van der Flier, L.G.; et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 2014, 507, 513–518. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hardtke, S.; Ohl, L.; Forster, R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 2005, 106, 1924–1931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tahiliani, V.; Hutchinson, T.E.; Abboud, G.; Croft, M.; Salek-Ardakani, S. OX40 Cooperates with ICOS To Amplify Follicular Th Cell Development and Germinal Center Reactions during Infection. J. Immunol. 2017, 198, 218–228. [Google Scholar] [CrossRef] [PubMed]
- Kerfoot, S.M.; Yaari, G.; Patel, J.R.; Johnson, K.L.; Gonzalez, D.G.; Kleinstein, S.H.; Haberman, A.M. Germinal center B cell and T follicular helper cell development initiates in the inter-follicular zone. Immunity 2011, 34, 947–960. [Google Scholar] [CrossRef] [PubMed]
- Baumjohann, D.; Preite, S.; Reboldi, A.; Ronchi, F.; Ansel, K.M.; Lanzavecchia, A.; Sallusto, F. Persistent Antigen and Germinal Center B Cells Sustain T Follicular Helper Cell Responses and Phenotype. Immunity 2013, 38, 596–605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keck, S.; Schmaler, M.; Ganter, S.; Wyss, L.; Oberle, S.; Huseby, E.S.; Zehn, D.; King, C.G. Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation. Proc. Natl. Acad. Sci. USA 2014, 111, 14852–14857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Choi, Y.S.; Eto, D.; Yang, J.A.; Lao, C.; Crotty, S. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 2013, 190, 3049–3053. [Google Scholar] [CrossRef] [PubMed]
- Eto, D.; Lao, C.; DiToro, D.; Barnett, B.; Escobar, T.C.; Kageyama, R.; Yusuf, I.; Crotty, S. IL-21 and IL-6 Are Critical for Different Aspects of B Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T Cell (Tfh) Differentiation. PLoS ONE 2011, 6, e17739. [Google Scholar] [CrossRef] [PubMed]
- Nakayamada, S.; Kanno, Y.; Takahashi, H.; Jankovic, D.; Lu, K.T.; Johnson, T.A.; Sun, H.W.; Vahedi, G.; Hakim, O.; Handon, R.; et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 2011, 35, 919–931. [Google Scholar] [CrossRef] [PubMed]
- Ma, C.S.; Suryani, S.; Avery, D.T.; Chan, A.; Nanan, R.; Santner-Nanan, B.; Deenick, E.K.; Tangye, S.G. Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol. Cell Biol. 2009, 87, 590–600. [Google Scholar] [CrossRef] [PubMed]
- Schmitt, N.; Morita, R.; Bourdery, L.; Bentebibel, S.-E.; Zurawski, S.M.; Banchereau, J.; Ueno, H. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009, 31, 158–169. [Google Scholar] [CrossRef] [PubMed]
- Nurieva, R.I.; Chung, Y.; Hwang, D.; Yang, X.O.; Kang, H.S.; Ma, L.; Wang, Y.H.; Watowich, S.S.; Jetten, A.M.; Tian, Q.; et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008, 29, 138–149. [Google Scholar] [CrossRef] [PubMed]
- Vogelzang, A.; McGuire, H.M.; Yu, D.; Sprent, J.; Mackay, C.R.; King, C. A Fundamental Role for Interleukin-21 in the Generation of T Follicular Helper Cells. Immunity 2008, 29, 127–137. [Google Scholar] [CrossRef] [PubMed]
- Schmitt, N.; Liu, Y.; Bentebibel, S.-E.; Munagala, I.; Bourdery, L.; Venuprasad, K.; Banchereau, J.; Ueno, H. The cytokine TGF-beta co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat. Immunol. 2014, 15, 856–865. [Google Scholar] [CrossRef] [PubMed]
- Harker, J.A.; Dolgoter, A.; Zuniga, E.I. Cell-intrinsic IL-27 and gp130 cytokine receptor signaling regulates virus-specific CD4+ T cell responses and viral control during chronic infection. Immunity 2013, 39, 548–559. [Google Scholar] [CrossRef] [PubMed]
- Batten, M.; Ramamoorthi, N.; Kljavin, N.M.; Ma, C.S.; Cox, J.H.; Dengler, H.S.; Danilenko, D.M.; Caplazi, P.; Wong, M.; Fulcher, D.A.; et al. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 2010, 207, 2895–2906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.K.; Silva, D.G.; Martin, J.L.; Pratama, A.; Hu, X.; Chang, P.-P.; Walters, G.; Vinuesa, C.G. Interferon-γ Excess Leads to Pathogenic Accumulation of Follicular Helper T Cells and Germinal Centers. Immunity 2012, 37, 880–892. [Google Scholar] [CrossRef] [PubMed]
- Suto, A.; Kashiwakuma, D.; Kagami, S.-I.; Hirose, K.; Watanabe, N.; Yokote, K.; Saito, Y.; Nakayama, T.; Grusby, M.J.; Iwamoto, I.; et al. Development and characterization of IL-21–producing CD4+ T cells. J. Exp. Med. 2008, 205, 1369–1379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McCarron, M.J.; Marie, J.C. TGF-beta prevents T follicular helper cell accumulation and B cell autoreactivity. J. Clin. Investig. 2014, 124, 4375–4386. [Google Scholar] [CrossRef] [PubMed]
- Locci, M.; Wu, J.E.; Arumemi, F.; Mikulski, Z.; Dahlberg, C.; Miller, A.T.; Crotty, S. Activin A programs the differentiation of human TFH cells. Nat. Immunol. 2016, 17, 976–984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jacquemin, C.; Schmitt, N.; Contin-Bordes, C.; Liu, Y.; Narayanan, P.; Seneschal, J.; Maurouard, T.; Dougall, D.; Davizon, E.S.; Dumortier, H.; et al. OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity 2015, 42, 1159–1170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Akiba, H.; Takeda, K.; Kojima, Y.; Usui, Y.; Harada, N.; Yamazaki, T.; Ma, J.; Tezuka, K.; Yagita, H.; Okumura, K. The Role of ICOS in the CXCR5+ Follicular B Helper T Cell Maintenance In Vivo. J. Immunol. 2005, 175, 2340–2348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Choi, Y.S.; Kageyama, R.; Eto, D.; Escobar, T.C.; Johnston, R.J.; Monticelli, L.; Lao, C.; Crotty, S. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 2011, 34, 932–946. [Google Scholar] [CrossRef] [PubMed]
- Bossaller, L.; Burger, J.; Draeger, R.; Grimbacher, B.; Knoth, R.; Plebani, A.; Durandy, A.; Baumann, U.; Schlesier, M.; Welcher, A.A.; et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 2006, 177, 4927–4932. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.J.; Heuts, F.; Ovcinnikovs, V.; Wardzinski, L.; Bowers, C.; Schmidt, E.M.; Kogimtzis, A.; Kenefeck, R.; Sansom, D.M.; Walker, L.S. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc. Natl. Acad. Sci. USA 2015, 112, 524–529. [Google Scholar] [CrossRef] [PubMed]
- Weber, J.P.; Fuhrmann, F.; Feist, R.K.; Lahmann, A.; Baz Al, M.S.; Gentz, L.-J.; Vu Van, D.; Mages, H.W.; Haftmann, C.; Riedel, R.; et al. ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. J. Exp. Med. 2015, 212, 217–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cannons, J.L.; Qi, H.; Lu, K.T.; Ghai, M.; Gomez-Rodriguez, J.; Cheng, J.; Wakeland, E.K.; Germain, R.N.; Schwartzberg, P.L. Optimal Germinal Center Responses Require A Multi-stage T:B Cell Adhesion Process Involving Integrins, SLAM-associated protein and CD84. Immunity 2010, 32, 253–265. [Google Scholar] [CrossRef] [PubMed]
- Crotty, S.; Kersh, E.N.; Cannons, J.; Schwartzberg, P.L.; Ahmed, R. SAP is required for generating long-term humoral immunity. Nature 2003, 421, 282–287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ballesteros-Tato, A.; León, B.; Graf, B.A.; Moquin, A.; Adams, P.S.; Lund, F.E.; Randall, T.D. Interleukin-2 inhibits germinal center formation by limiting T follicular helper differentiation. Immunity 2012, 36, 847–856. [Google Scholar] [CrossRef] [PubMed]
- Johnston, R.J.; Choi, Y.S.; Diamond, J.A.; Yang, J.A.; Crotty, S. STAT5 is a potent negative regulator of T FHcell differentiation. J. Exp. Med. 2012, 209, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Oestreich, K.J.; Mohn, S.E.; Weinmann, A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 2012, 13, 405–411. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McDonald, P.W.; Read, K.A.; Baker, C.E.; Anderson, A.E.; Powell, M.D.; Ballesteros-Tato, A.; Oestreich, K.J. IL-7 signalling represses Bcl-6 and the TFH gene program. Nat. Commun. 2016, 7, 10285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sage, P.T.; Paterson, A.M.; Lovitch, S.B.; Sharpe, A.H. The Coinhibitory Receptor CTLA-4 Controls B Cell Responses by Modulating T Follicular Helper, T Follicular Regulatory, and T Regulatory Cells. Immunity 2014, 41, 1026–1039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- MacLennan, I.C.M.; Toellner, K.M.; Cunningham, A.F.; Serre, K.; Sze, D.M.Y.; Zúñiga, E.; Cook, M.C.; Vinuesa, C.G. Extrafollicular antibody responses. Immunol. Rev. 2003, 194, 8–18. [Google Scholar] [CrossRef] [PubMed]
- Schwickert, T.A.; Victora, G.D.; Fooksman, D.R.; Kamphorst, A.O.; Mugnier, M.R.; Gitlin, A.D.; Dustin, M.L.; Nussenzweig, M.C. A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 2011, 208, 1243–1252. [Google Scholar] [CrossRef] [PubMed]
- Victora, G.D.; Schwickert, T.A.; Fooksman, D.R.; Kamphorst, A.O.; Meyer-Hermann, M.; Dustin, M.L.; Nussenzweig, M.C. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 2010, 143, 592–605. [Google Scholar] [CrossRef] [PubMed]
- Gitlin, A.D.; Shulman, Z.; Nussenzweig, M.C. Clonal selection in the germinal center by regulated proliferation and hypermutation. Nature 2014, 509, 637–640. [Google Scholar] [CrossRef] [PubMed]
- Moens, L.; Tangye, S.G. Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage. Front. Immunol. 2014, 5, 65. [Google Scholar] [CrossRef] [PubMed]
- Kräutler, N.J.; Suan, D.; Butt, D.; Bourne, K.; Hermes, J.R.; Chan, T.D.; Sundling, C.; Kaplan, W.; Schofield, P.; Jackson, J.; et al. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J. Exp. Med. 2017, 214, 1259–1267. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Tech, L.; George, L.A.; Acs, A.; Durrett, R.E.; Hess, H.; Walker, L.S.K.; Tarlinton, D.M.; Fletcher, A.L.; Hauser, A.E.; et al. Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells. J. Exp. Med. 2018, 215, 1227–1243. [Google Scholar] [CrossRef] [PubMed]
- Zotos, D.; Coquet, J.M.; Zhang, Y.; Light, A.; D’Costa, K.; Kallies, A.; Corcoran, L.M.; Godfrey, D.I.; Toellner, K.M.; Smyth, M.J.; et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 2010, 207, 365–378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Linterman, M.A.; Beaton, L.; Yu, D.; Ramiscal, R.R.; Srivastava, M.; Hogan, J.J.; Verma, N.K.; Smyth, M.J.; Rigby, R.J.; Vinuesa, C.G. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 2010, 207, 353–363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Avery, D.T.; Bryant, V.L.; Ma, C.S.; de Waal Malefyt, R.; Tangye, S.G. IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J. Immunol. 2008, 181, 1767–1779. [Google Scholar] [CrossRef] [PubMed]
- Reinhardt, R.L.; Liang, H.-E.; Locksley, R.M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 2009, 10, 385–393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rousset, F.; Garcia, E.; Defrance, T.; Péronne, C.; Vezzio, N.; Hsu, D.H.; Kastelein, R.; Moore, K.W.; Banchereau, J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 1992, 89, 1890–1893. [Google Scholar] [CrossRef] [PubMed]
- Choe, J.; Choi, Y.S. IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur. J. Immunol. 1998, 28, 508–515. [Google Scholar] [CrossRef] [Green Version]
- Elgueta, R.; Benson, M.J.; de Vries, V.C.; Wasiuk, A.; Guo, Y.; Noelle, R.J. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 2009, 229. [Google Scholar] [CrossRef] [PubMed]
- Fazilleau, N.; Eisenbraun, M.D.; Malherbe, L.; Ebright, J.N.; Pogue-Caley, R.R.; McHeyzer-Williams, L.J.; McHeyzer-Williams, M.G. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 2007, 8, 753. [Google Scholar] [CrossRef] [PubMed]
- Morita, R.; Schmitt, N.; Bentebibel, S.-E.; Ranganathan, R.; Bourdery, L.; Zurawski, G.; Foucat, E.; Dullaers, M.; Oh, S.; Sabzghabaei, N.; et al. Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion. Immunity 2011, 34, 108–121. [Google Scholar] [CrossRef] [PubMed]
- Locci, M.; Havenar-Daughton, C.; Landais, E.; Wu, J.; Kroenke, M.A.; Arlehamn, C.L.; Su, L.F.; Cubas, R.; Sette, A.; Haddad, E.K.; et al. Human Circulating PD-1+CXCR3-CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses. Immunity 2013, 39, 758–769. [Google Scholar] [CrossRef] [PubMed]
- Simpson, N.; Gatenby, P.A.; Wilson, A.; Malik, S.; Fulcher, D.A.; Tangye, S.G.; Manku, H.; Vyse, T.J.; Roncador, G.; Huttley, G.A.; et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010, 62, 234–244. [Google Scholar] [PubMed] [Green Version]
- Sage, P.T.; Alvarez, D.; Godec, J.; von Andrian, U.H.; Sharpe, A.H. Circulating T follicular regulatory and helper cells have memory-like properties. The Journal of Clinical Investigation. Am. Soc. Clin. Investig. 2014, 124, 5191–5204. [Google Scholar] [CrossRef] [PubMed]
- Heit, A.; Schmitz, F.; Gerdts, S.; Flach, B.; Moore, M.S.; Perkins, J.A.; Harlan, S.R.; Aderem, A.; Spearman, P.; Tomaras, G.D.; et al. Vaccination establishes clonal relatives of germinal center T cells in the blood of humans. J. Exp. Med. 2017, 214, 2139–2152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bentebibel, S.E.; Lopez, S.; Obermoser, G.; Schmitt, N.; Mueller, C.; Harrod, C.; Flano, E.; Mejias, A.; Albrecht, R.A.; Blankenship, D.; et al. Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates with Antibody Responses to Influenza Vaccination. Sci. Transl. Med. 2013, 5, 176ra32-2. [Google Scholar] [CrossRef] [PubMed]
- Velu, V.; Mylvaganam, G.H.; Gangadhara, S.; Hong, J.J.; Iyer, S.S.; Gumber, S.; Ibegbu, C.C.; Villinger, F.; Amara, R.R. Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells. J. Immunol. 2016, 197, 1832–1842. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nance, J.P.; Bélanger, S.; Johnston, R.J.; Hu, J.K.; Takemori, T.; Crotty, S. Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3. Proc. Natl. Acad. Sci. USA 2015, 112, 13324–13329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Preite, S.; Baumjohann, D.; Foglierini, M.; Basso, C.; Ronchi, F.; Fernandez Rodriguez, B.M.; Corti, D.; Lanzavecchia, A.; Sallusto, F. Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells. Eur. J. Immunol. 2015, 45, 3010–3021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vinuesa, C.G.; Cook, M.C.; Angelucci, C.; Athanasopoulos, V.; Rui, L.; Hill, K.M.; Yu, D.; Domaschenz, H.; Whittle, B.; Lambe, T.; et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 2005, 435, 452–458. [Google Scholar] [CrossRef] [PubMed]
- Choi, Y.S.; Yang, J.A.; Yusuf, I.; Johnston, R.J.; Greenbaum, J.; Peters, B.; Crotty, S. Bcl6 Expressing Follicular Helper CD4 T Cells Are Fate Committed Early and Have the Capacity To Form Memory. J. Immunol. 2013, 190, 4014–4026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sage, P.T.; Francisco, L.M.; Carman, C.V.; Sharpe, A.H. PD-1 controls Lymph Node and Blood T Follicular Regulatory Cells. Nat. Immunol. 2013, 14, 152–161. [Google Scholar] [CrossRef] [PubMed]
- Good-Jacobson, K.L.; Szumilas, C.G.; Chen, L.; Sharpe, A.H.; Tomayko, M.M.; Shlomchik, M.J. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 2010, 11, 535–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Butler, N.S.; Moebius, J.; Pewe, L.L.; Traore, B.; Doumbo, O.K.; Tygrett, L.T.; Waldschmidt, T.J.; Crompton, P.D.; Harty, J.T. Therapeutic PD-L1 and LAG-3 blockade rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 2012, 13, 188–195. [Google Scholar] [CrossRef] [PubMed]
- Hams, E.; McCarron, M.J.; Amu, S.; Yagita, H.; Azuma, M.; Chen, L.; Fallon, P.G. Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J. Immunol. 2011, 186, 5648–5655. [Google Scholar] [CrossRef] [PubMed]
- Linterman, M.A.; Pierson, W.; Lee, S.K.; Kallies, A.; Kawamoto, S.; Rayner, T.F.; Srivastava, M.; Divekar, D.P.; Beaton, L.; Hogan, J.J.; et al. Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response. Nat. Med. 2011, 17, 975–982. [Google Scholar] [CrossRef] [PubMed]
- Wollenberg, I.; Agua-Doce, A.; Hernandez, A.; Almeida, C.; Oliveira, V.G.; Faro, J.; Graca, L. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 2011, 187, 4553–4560. [Google Scholar] [CrossRef] [PubMed]
- Chung, Y.; Tanaka, S.; Chu, F.; Nurieva, R.; Martinez, G.J.; Rawal, S.; Wang, Y.-H.; Lim, H.Y.; Reynolds, J.M.; Zhou, X.-H.; et al. Follicular regulatory T (Tfr) cells with dual Foxp3 and Bcl6 expression suppress germinal center reactions. Nat. Med. 2011, 17, 983–988. [Google Scholar] [CrossRef] [PubMed]
- Sage, P.T.; Ron-Harel, N.; Juneja, V.R.; Sen, D.R.; Maleri, S.; Sungnak, W.; Kuchroo, V.K.; Haining, W.N.; Chevrier, N.; Haigis, M.; et al. Suppression by TFR cells leads to durable and selective inhibition of B cell effector function. Nat. Immunol. 2016, 17, 1436–1446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sage, P.T.; Sharpe, A.H. T follicular regulatory cells in the regulation of B cell responses. Trends Immunol. 2015, 36, 410–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perreau, M.; Savoye, A.-L.; De Crignis, E.; Corpataux, J.-M.; Cubas, R.; Haddad, E.K.; De Leval, L.; Graziosi, C.; Pantaleo, G. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 2013, 210, 143–156. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Weatherall, C.; Bailey, M.; Alcantara, S.; De Rose, R.; Estaquier, J.; Wilson, K.; Suzuki, K.; Corbeil, J.; Cooper, D.A.; et al. Simian Immunodeficiency Virus Infects Follicular Helper CD4 T Cells in Lymphoid Tissues during Pathogenic Infection of Pigtail Macaques. J. Virol. 2013, 87, 3760–3773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kohler, S.L.; Pham, M.N.; Folkvord, J.M.; Arends, T.; Miller, S.M.; Miles, B.; Meditz, A.L.; McCarter, M.; Levy, D.N.; Connick, E. Germinal Center T Follicular Helper Cells Are Highly Permissive to HIV-1 and Alter Their Phenotype during Virus Replication. J. Immunol. 2016, 196, 2711–2722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lindqvist, M.; van Lunzen, J.; Soghoian, D.Z.; Kuhl, B.D.; Ranasinghe, S.; Kranias, G.; Flanders, M.D.; Cutler, S.; Yudanin, N.; Muller, M.I.; et al. Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J. Clin. Investig. 2012, 122, 3271–3280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wendel, B.S.; del Alcazar, D.; He, C.; Del Río-Estrada, P.M.; Aiamkitsumrit, B.; Ablanedo-Terrazas, Y.; Hernandez, S.M.; Ma, K.-Y.; Betts, M.R.; Pulido, L.; et al. The receptor repertoire and functional profile of follicular T cells in HIV-infected lymph nodes. Sci. Immunol. 2018, 3, eaan8884. [Google Scholar] [CrossRef] [PubMed]
- Fahey, L.M.; Wilson, E.B.; Elsaesser, H.; Fistonich, C.D.; McGavern, D.B.; Brooks, D.G. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 2011, 208, 987–999. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Raziorrouh, B.; Sacher, K.; Tawar, R.G.; Emmerich, F.; Neumann-Haefelin, C.; Baumert, T.F.; Thimme, R.; Boettler, T. Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients with Acute and Chronic HCV Infections. Gastroenterology 2016, 150, 696–706. [Google Scholar] [CrossRef] [PubMed]
- Colineau, L.; Rouers, A.; Yamamoto, T.; Xu, Y.; Urrutia, A.; Pham, H.-P.; Cardinaud, S.; Samri, a.; Dorgham, K.; Coulon, P.-G.; et al. HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation. PLoS ONE 2015, 10, e0140978-19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cubas, R.A.; Mudd, J.C.; Savoye, A.-L.; Perreau, M.; van Grevenynghe, J.; Metcalf, T.; Connick, E.; Meditz, A.; Freeman, G.J.; Abesada-Terk, G., Jr.; et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat. Med. 2013, 19, 494–499. [Google Scholar] [CrossRef] [PubMed]
- Boswell, K.L.; Paris, R.; Boritz, E.; Ambrozak, D.; Yamamoto, T.; Darko, S.; Wloka, K.; Wheatley, A.; Narpala, S.; McDermott, A.; et al. Loss of Circulating CD4 T Cells with B Cell Helper Function during Chronic HIV Infection. PLoS Pathog. 2014, 10, e1003853-14. [Google Scholar] [CrossRef] [PubMed]
- Cubas, R.; van Grevenynghe, J.; Wills, S.; Kardava, L.; Santich, B.H.; Buckner, C.M.; Muir, R.; Tardif, V.; Nichols, C.; Procopio, F.; et al. Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection. J. Immunol. 2015, 195, 5625–5636. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamamoto, T.; Lynch, R.M.; Gautam, R.; Matus-Nicodemos, R.; Schmidt, S.D.; Boswell, K.L.; Darko, S.; Wong, P.; Sheng, Z.; Petrovas, C.; et al. Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection. Sci. Transl. Med. 2015, 7, 298ra120-0. [Google Scholar] [CrossRef] [PubMed]
- Moody, M.A.; Pedroza-Pacheco, I.; Vandergrift, N.A.; Chui, C.; Lloyd, K.E.; Parks, R.; Soderberg, K.A.; Ogbe, A.T.; Cohen, M.S.; Liao, H.-X.; et al. Immune perturbations in HIV-1-infected individuals who make broadly neutralizing antibodies. Sci. Immunol. 2016, 1, aag0851. [Google Scholar] [CrossRef] [PubMed]
- Havenar-Daughton, C.; Lindqvist, M.; Heit, A.; Wu, J.E.; Reiss, S.M.; Kendric, K.; Bélanger, S.; Kasturi, S.P.; Landais, E.; Akondy, R.S.; et al. CXCL13 is a plasma biomarker of germinal center activity. Proc. Natl. Acad. Sci. USA 2016, 113, 2702–2707. [Google Scholar] [CrossRef] [PubMed]
- Cohen, K.; Altfeld, M.; Alter, G.; Stamatatos, L. Early Preservation of CXCR5+ PD-1+ Helper T Cells and B Cell Activation Predict the Breadth of Neutralizing Antibody Responses in Chronic HIV-1 Infection. J. Virol. 2014, 88, 13310–13321. [Google Scholar] [CrossRef] [PubMed]
- Mabuka, J.M.; Dugast, A.-S.; Muema, D.M.; Reddy, T.; Ramlakhan, Y.; Euler, Z.; Ismail, N.; Moodley, A.; Dong, K.L.; Morris, L.; et al. Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies. Front. Immunol. 2017, 8, 1104. [Google Scholar] [CrossRef] [PubMed]
- Dan, J.M.; Lindestam Arlehamn, C.S.; Weiskopf, D.; da Silva Antunes, R.; Havenar-Daughton, C.; Reiss, S.M.; Brigger, M.; Bothwell, M.; Sette, A.; Crotty, S. A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood. J. Immunol. 2016, 197, 983–993. [Google Scholar] [CrossRef] [PubMed]
- Reiss, S.; Baxter, A.E.; Cirelli, K.M.; Dan, J.M.; Morou, A.; Daigneault, A.; Brassard, N.; Silvestri, G.; Routy, J.-P.; Havenar-Daughton, C.; et al. Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS ONE 2017, 12, e0186998. [Google Scholar] [CrossRef] [PubMed]
- Havenar-Daughton, C.; Reiss, S.M.; Carnathan, D.G.; Wu, J.E.; Kendric, K.; Torrents de la Pena, A.; Pai Kasturi, S.; Dan, J.M.; Bothwell, M.; Sanders, R.W.; et al. Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique. J. Immunol. 2016, 197, 994–1002. [Google Scholar] [CrossRef] [PubMed]
- Liang, F.; Lindgren, G.; Sandgren, K.J.; Thompson, E.A.; Francica, J.R.; Seubert, A.; De Gregorio, E.; Barnett, S.; O’Hagan, D.T.; Sullivan, N.J.; et al. Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci. Transl. Med. 2017, 9, eaal2094. [Google Scholar] [CrossRef] [PubMed]
- Desbien, A.L.; Dubois Cauwelaert, N.; Reed, S.J.; Bailor, H.R.; Liang, H.; Carter, D.; Duthie, M.S.; Fox, C.B.; Reed, S.G.; Orr, M.T. IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants. J. Immunol. 2016, 197, 4351–4359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ugolini, M.; Gerhard, J.; Burkert, S.; Jensen, K.J.; Georg, P.; Ebner, F.; Volkers, S.M.; Thada, S.; Dietert, K.; Bauer, L.; et al. Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nat. Immunol. 2018, 19, 386–396. [Google Scholar] [CrossRef] [PubMed]
- Rookhuizen, D.C.; DeFranco, A.L. Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses. Proc. Natl. Acad. Sci. USA 2014, 111, E3224–E3233. [Google Scholar] [CrossRef] [PubMed]
- Madan-Lala, R.; Pradhan, P.; Roy, K. Combinatorial Delivery of Dual and Triple TLR Agonists via Polymeric Pathogen-like Particles Synergistically Enhances Innate and Adaptive Immune Responses. Sci. Rep. 2017, 7, 2530. [Google Scholar] [CrossRef] [PubMed]
- Dowling, J.K.; Mansell, A. Toll-like receptors: The swiss army knife of immunity and vaccine development. Clin. Trans. Immunol. 2016, 5, e85. [Google Scholar] [CrossRef] [PubMed]
- Brahmakshatriya, V.; Kuang, Y.; Devarajan, P.; Xia, J.; Zhang, W.; Vong, A.M.; Swain, S.L. IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo. J. Immunol. 2017, 198, 2819–2833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Radtke, A.J.; Anderson, C.F.; Riteau, N.; Rausch, K.; Scaria, P.; Kelnhofer, E.R.; Howard, R.F.; Sher, A.; Germain, R.N.; Duffy, P. Adjuvant and carrier protein-dependent T-cell priming promotes a robust antibody response against the Plasmodium falciparum Pfs25 vaccine candidate. Sci. Rep. 2017, 7, 40312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pauthner, M.; Havenar-Daughton, C.; Sok, D.; Nkolola, J.P.; Bastidas, R.; Boopathy, A.V.; Carnathan, D.G.; Chandrashekar, A.; Cirelli, K.M.; Cottrell, C.A.; et al. Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches. Immunity 2017, 46, 1073–1076. [Google Scholar] [CrossRef] [PubMed]
- Koutsonanos, D.G.; Esser, E.S.; McMaster, S.R.; Kalluri, P.; Lee, J.-W.; Prausnitz, M.R.; Skountzou, I.; Denning, T.L.; Kohlmeier, J.E.; Compans, R.W. Enhanced immune responses by skin vaccination with influenza subunit vaccine in young hosts. Vaccine 2015, 33, 4675–4682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krishnaswamy, J.K.; Gowthaman, U.; Zhang, B.; Mattsson, J.; Szeponik, L.; Liu, D.; Wu, R.; White, T.; Calabro, S.; Xu, L.; et al. Migratory CD11b +conventional dendritic cells induce T follicular helper cell–dependent antibody responses. Sci. Immunol. 2017, 2, eaam9169. [Google Scholar] [CrossRef] [PubMed]
- Tuero, I.; Robert-Guroff, M. Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models. Viruses 2014, 6, 3129–3158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tam, H.H.; Melo, M.B.; Kang, M.; Pelet, J.M.; Ruda, V.M.; Foley, M.H.; Hu, J.K.; Kumari, S.; Crampton, J.; Baldeon, A.D.; et al. Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc. Natl. Acad. Sci. USA 2016, 113, E6639–E6648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pardi, N.; Hogan, M.J.; Naradikian, M.S.; Parkhouse, K.; Cain, D.W.; Jones, L.; Moody, M.A.; Verkerke, H.P.; Myles, A.; Willis, E.; et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 2018, 136, jem.20171450. [Google Scholar] [CrossRef] [PubMed]
- Wing, J.B.; Ise, W.; Kurosaki, T.; Sakaguchi, S. Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4. Immunity 2014, 41, 1013–1025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.; Nguyen, M.T. Recent Advances of Vaccine Adjuvants for Infectious Diseases. Immune Netw. 2015, 15, 51–57. [Google Scholar] [CrossRef] [PubMed]
- Vesikari, T.; Knuf, M.; Wutzler, P.; Karvonen, A.; Kieninger-Baum, D.; Schmitt, H.-J.; Baehner, F.A.; Borkowski, A.; Tsai, T.F.; Clemens, R. Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children. N. Engl. J. Med. 2011, 365, 1406–1416. [Google Scholar] [CrossRef] [PubMed]
- Domnich, A.; Arata, L.; Amicizia, D.; Puig-Barbera, J.; Gasparini, R.; Panatto, D. Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis. Vaccine 2017, 35, 513–520. [Google Scholar] [CrossRef] [PubMed]
- Galli, G.; Hancock, K.; Hoschler, K.; DeVos, J.; Praus, M.; Bardelli, M.; Malzone, C.; Castellino, F.; Gentile, C.; McNally, T.; et al. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc. Natl. Acad. Sci. USA 2009, 106, 7962–7967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khurana, S.; Verma, N.; Yewdell, J.W.; Hilbert, A.K.; Castellino, F.; Lattanzi, M.; Del Giudice, G.; Rappuoli, R.; Golding, H. MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines. Sci. Transl. Med. 2011, 3, 85ra48-8. [Google Scholar] [CrossRef] [PubMed]
- Spensieri, F.; Siena, E.; Borgogni, E.; Zedda, L.; Cantisani, R.; Chiappini, N.; Schiavetti, F.; Rosa, D.; Castellino, F.; Montomoli, E.; et al. Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans. PLoS ONE 2016, 11, e0157066. [Google Scholar] [CrossRef] [PubMed]
- Rerks-Ngarm, S.; Pitisuttithum, P.; Nitayaphan, S.; Kaewkungwal, J.; Chiu, J.; Paris, R.; Premsri, N.; Namwat, C.; de Souza, M.; Adams, E.; et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N. Engl. J. Med. 2009, 361, 2209–2220. [Google Scholar] [CrossRef] [PubMed]
- Schultz, B.T.; Teigler, J.E.; Pissani, F.; Oster, A.F.; Kranias, G.; Alter, G.; Marovich, M.; Eller, M.A.; Dittmer, U.; Robb, M.L.; et al. Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions. Immunity 2016, 44, 167–178. [Google Scholar] [CrossRef] [PubMed]
- Vaccari, M.; Gordon, S.N.; Fourati, S.; Schifanella, L.; Liyanage, N.P.M.; Cameron, M.; Keele, B.F.; Shen, X.; Tomaras, G.D.; Bilings, E.; et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat. Med. 2016, 22, 762–770. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kasturi, S.P.; Kozlowski, P.A.; Nakaya, H.I.; Burger, M.C.; Russo, P.; Pham, M.; Kovalenkov, Y.; Silveira, E.L.V.; Havenar-Daughton, C.; Burton, S.L.; et al. Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques. J. Virol. 2017, 91, e01844-16. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Fernandez, C.; Alcantara, S.; Bailey, M.; De Rose, R.; Kelleher, A.D.; Zaunders, J.; Kent, S.J. Serial study of lymph node cell subsets using fine needle aspiration in pigtail macaques. J. Immunol. Methods 2013, 394, 73–83. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Wang, W.; Wang, S. Effect of Vaccine Administration Modality on Immunogenicity and Efficacy. Expert Rev. Vaccines 2015, 14, 1509–1523. [Google Scholar] [CrossRef] [PubMed]
- Su, F.; Patel, G.B.; Hu, S.; Chen, W. Induction of mucosal immunity through systemic immunization: Phantom or reality? Hum. Vaccines Immunother. 2016, 12, 1070–1079. [Google Scholar] [CrossRef] [PubMed]
- Remarque, E.J.; van Beek, W.C.; Ligthart, G.J.; Borst, R.J.; Nagelkerken, L.; Palache, A.M.; Sprenger, M.J.W.; Masurel, N. Improvement of the immunoglobulin subclass response to influenza vaccine in elderly nursing-home residents by the use of high-dose vaccines. Vaccine 1993, 11, 649–654. [Google Scholar] [CrossRef]
- Pilkinton, M.A.; Nicholas, K.J.; Warren, C.M.; Smith, R.M.; Yoder, S.M.; Talbot, H.K.; Kalams, S.A. Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion. Vaccine 2017, 35, 329–336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pardi, N.; Hogan, M.J.; Porter, F.W.; Weissman, D. mRNA vaccines—A new era in vaccinology. Nat. Rev. Drug Discov. 2018, 17, 261–279. [Google Scholar] [CrossRef] [PubMed]
- Nishimura, Y.; Martin, M.A. Of Mice, Macaques, and Men: Broadly Neutralizing Antibody Immunotherapy for HIV-1. Cell Host Microbe 2017, 22, 207–216. [Google Scholar] [CrossRef] [PubMed]
Signalling Molecule/Receptor Pair | Species | Role in Tfh Differentiation | Source/Interacting Cell Type | References |
---|---|---|---|---|
IL-6/IL-6R | Mouse | Promotion | DCs, B cells | [24,25] |
IL-12/IL-12R | Mouse, human | Promotion | DCs | [26,27,28] |
IL-21/Il-21R | Mouse | Promotion | T cells | [29,30] |
IL-23/IL-23R | Human | Promotion | DCs | [31] |
IL-27/IL-27R | Mouse | Promotion | DCs | [32,33] |
IFN-γ/IFN-γR | Mouse | Promotion | T cells | [34] |
TGF-β/TGF-βR | Mouse, human | Inhibition (mouse), Promotion (human) | DCs | [31,35,36] |
Activin A/Activin-R | Human | Promotion | DCs | [37] |
Ox40L/Ox40 | Mouse, human | Promotion | DCs, B cells | [20,38] |
ICOSL/ICOS | Mouse, human | Promotion | B cells | [39,40,41] |
B7/CD28 | Mouse | Promotion | DCs, B cells | [42,43] |
SLAM family members | Mouse, human | Promotion | B cells | [44,45] |
IL-2/IL-2R | Mouse, human | Inhibition | T cells | [37,46,47,48] |
IL-7/IL-7R | Mouse | Inhibition | DCs | [49] |
B7/CTLA-4 | Mouse | Inhibition | - | [42,50] |
Tfh Functional Molecule | Effect on B Cells | References |
---|---|---|
IL-21 | CSR, activation, proliferation, SHM, plasma cell differentiation | [57,58,59] |
IL-4 | Proliferation, CSR, SHM | [60,61] |
IL-10 | Proliferation, CSR, plasma cell differentiation | [62,63] |
CD40L | Activation, proliferation, CSR | [64] |
Vaccine Component | Strategy | Result | Effect on Tfh | Potential Caveat | References |
---|---|---|---|---|---|
Adjuvant | Alum + TLR agonists, MF59 | Enhanced APC recruitment to infection site and elevated antigen delivery to LN | Tfh differentiation and maintenance | Increased immunogenicity might cause increased local and systemic adverse effects | [105] |
Various vaccine formulations containing TLR agonists | Induction of Tfh-promoting signals in DCs | Tfh differentiation | [106,107,108,109,110,111,112] | ||
Reduction of Tfr/Tfh ratio | Enhanced Tfh function | ||||
Route of vaccination | Subcutaneous vs. intramuscular | Enhanced drainage of soluble antigen | Tfh differentiation and maintenance | Overabundant Tfh might lead to the selection of low affinity B cell clones (also applies to other strategies) | [113,114,115,116] |
Intradermal vs. intramuscular | Targeting of higher DC number | Tfh differentiation | |||
Mucosal alone or in combination with systemic | Enhancing mucosal antibody responses | Direct site of humoral response | |||
Enhanced or extended antigen delivery | Increased antigen dose, prolonged antigen delivery using multiple injections, osmotic pumps or mRNA systems | Enhanced DC-naïve CD4 interaction that promotes Tfh differentiation, sustained availability of antigen on FDCs | Tfh differentiation and maintenance | Excessive long-term antigen persistence may be detrimental (exhaustion) | [22,113,117,118] |
Inhibition of negative regulators of Tfh | CTLA-4 blockade | Limit suppressive function of Tfr, direct effect on Tfh | Enhanced Tfh function | Systemic blockade of immune checkpoints can have serious side effects-local blockade at site of delivery might be an alternative | [50,119] |
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Niessl, J.; Kaufmann, D.E. Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development. Viruses 2018, 10, 336. https://doi.org/10.3390/v10060336
Niessl J, Kaufmann DE. Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development. Viruses. 2018; 10(6):336. https://doi.org/10.3390/v10060336
Chicago/Turabian StyleNiessl, Julia, and Daniel E. Kaufmann. 2018. "Harnessing T Follicular Helper Cell Responses for HIV Vaccine Development" Viruses 10, no. 6: 336. https://doi.org/10.3390/v10060336