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Cells
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T Cells: Differentiation and Function in Immunity and Disease
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T Cells: Differentiation and Function in Immunity and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15465

Special Issue Editors

Dr. Jazmina Libertad Gonzalez Cruz

E-Mail Website
Guest Editor
Faculty of Medicine, The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
Interests: T-cell epitopes; tumour vaccine; cancer immunotherapies; precision medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Graham Leggatt

E-Mail Website
Guest Editor
Faculty of Medicine, The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
Interests: CD8 T cells; T cell functional activity; skin immunology; tumour immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

T cells have a central role in adaptive immunity, and are essential for tumour surveillance as well as response to allergens and pathogens. The balance between the development of T cells and their target recognition is essential for effective immune responses, the maintenance of homeostasis and the generation of immunological memory. In this review, we will discuss new insights into how T cells develop and provide essential protection in different health and disease models. We will also investigate the influence of tissue localization, interaction with other cells and subset delineation in determining T cell roles, and how new therapies harness the potential of these cells to prevent immunopathology, trigger protective immunity through vaccines or therapeutic effect through immunomodulatory drugs.

This Special Issue will examine the development of diverse T-cell subpopulations; in vivo and in vitro models to study T-cell biology and vaccinology; T-cell roles in disease and health; the interplay between T cells and other immune subsets; and new therapeutic or prophylactic approaches that utilize T cells as central players to provide a beneficial effect.

Dr. Jazmina Libertad Gonzalez Cruz
Dr. Graham Leggatt
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • T cells
  • immunotherapy
  • immune memory
  • adaptive immunity
  • T-cell development
  • T-cell differentiation
  • immune modulators
  • T-cell animal models
  • autoimmunity
  • vaccines
  • cancer
  • infection

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Published Papers (6 papers)

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Research

17 pages, 6741 KiB  
Article
Nanoscale CAR Organization at the Immune Synapse Correlates with CAR-T Effector Functions
by Julia Sajman, Oren Yakovian, Naamit Unger Deshet, Shaked Almog, Galit Horn, Tova Waks, Anat Globerson Levin and Eilon Sherman
Cells 2023, 12(18), 2261; https://doi.org/10.3390/cells12182261 - 12 Sep 2023
Cited by 5 | Viewed by 2193
Abstract
T cells expressing chimeric antigen receptors (CARs) are at the forefront of clinical treatment of cancers. Still, the nanoscale organization of CARs at the interface of CAR-Ts with target cells, which is essential for TCR-mediated T cell activation, remains poorly understood. Here, we [...] Read more.
T cells expressing chimeric antigen receptors (CARs) are at the forefront of clinical treatment of cancers. Still, the nanoscale organization of CARs at the interface of CAR-Ts with target cells, which is essential for TCR-mediated T cell activation, remains poorly understood. Here, we studied the nanoscale organization of CARs targeting CD138 proteoglycans in such fixed and live interfaces, generated optimally for single-molecule localization microscopy. CARs showed significant self-association in nanoclusters that was enhanced in interfaces with on-target cells (SKOV-3, CAG, FaDu) relative to negative cells (OVCAR-3). CARs also segregated more efficiently from the abundant membrane phosphatase CD45 in CAR-T cells forming such interfaces. CAR clustering and segregation from CD45 correlated with the effector functions of Ca++ influx and target cell killing. Our results shed new light on the nanoscale organization of CARs on the surfaces of CAR-Ts engaging on- and off-target cells, and its potential significance for CAR-Ts’ efficacy and safety. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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21 pages, 3516 KiB  
Article
Skin-Grafting and Dendritic Cell “Boosted” Humanized Mouse Models Allow the Pre-Clinical Evaluation of Therapeutic Cancer Vaccines
by Bijun Zeng, Davide Moi, Lynn Tolley, Natalie Molotkov, Ian Hector Frazer, Christopher Perry, Riccardo Dolcetti, Roberta Mazzieri and Jazmina L. G. Cruz
Cells 2023, 12(16), 2094; https://doi.org/10.3390/cells12162094 - 18 Aug 2023
Viewed by 2653
Abstract
Vaccines have been hailed as one of the most remarkable medical advancements in human history, and their potential for treating cancer by generating or expanding anti-tumor T cells has garnered significant interest in recent years. However, the limited efficacy of therapeutic cancer vaccines [...] Read more.
Vaccines have been hailed as one of the most remarkable medical advancements in human history, and their potential for treating cancer by generating or expanding anti-tumor T cells has garnered significant interest in recent years. However, the limited efficacy of therapeutic cancer vaccines in clinical trials can be partially attributed to the inadequacy of current preclinical mouse models in recapitulating the complexities of the human immune system. In this study, we developed two innovative humanized mouse models to assess the immunogenicity and therapeutic effectiveness of vaccines targeting human papillomavirus (HPV16) antigens and delivering tumor antigens to human CD141+ dendritic cells (DCs). Both models were based on the transference of human peripheral blood mononuclear cells (PBMCs) into immunocompromised HLA-A*02-NSG mice (NSG-A2), where the use of fresh PBMCs boosted the engraftment of human cells up to 80%. The dynamics of immune cells in the PBMC-hu-NSG-A2 mice demonstrated that T cells constituted the vast majority of engrafted cells, which progressively expanded over time and retained their responsiveness to ex vivo stimulation. Using the PBMC-hu-NSG-A2 system, we generated a hyperplastic skin graft model expressing the HPV16-E7 oncogene. Remarkably, human cells populated the skin grafts, and upon vaccination with a DNA vaccine encoding an HPV16-E6/E7 protein, rapid rejection targeted to the E7-expressing skin was detected, underscoring the capacity of the model to mount a vaccine-specific response. To overcome the decline in DC numbers observed over time in PBMC-hu-NSG-A2 animals, we augmented the abundance of CD141+ DCs, the specific targets of our tailored nanoemulsions (TNEs), by transferring additional autologous PBMCs pre-treated in vitro with the growth factor Flt3-L. The Flt3-L treatment bolstered CD141+ DC numbers, leading to potent antigen-specific CD4+ and CD8+ T cell responses in vivo, which caused the regression of pre-established triple-negative breast cancer and melanoma tumors following CD141+ DC-targeting TNE vaccination. Notably, using HLA-A*02-matching PBMCs for humanizing NSG-A2 mice resulted in a delayed onset of graft-versus-host disease and enhanced the efficacy of the TNE vaccination compared with the parental NSG strain. In conclusion, we successfully established two humanized mouse models that exhibited strong antigen-specific responses and demonstrated tumor regression following vaccination. These models serve as valuable platforms for assessing the efficacy of therapeutic cancer vaccines targeting HPV16-dysplastic skin and diverse tumor antigens specifically delivered to CD141+ DCs. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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15 pages, 1885 KiB  
Article
Persistent CD8 T Cell Marks Caused by the HCMV Infection in Seropositive Adults: Prevalence of HLA-E-Reactive CD8 T Cells
by Amélie Rousselière and Béatrice Charreau
Cells 2023, 12(6), 889; https://doi.org/10.3390/cells12060889 - 14 Mar 2023
Cited by 2 | Viewed by 2284
Abstract
This study investigated the frequency and peptide specificity of long-lasting HCMV-specific CD8 T cells in a cohort of 120 cytomegalovirus seropositive (HCMV+) healthy carriers with the aim of deciphering the relative contribution of unconventional HLA-E- versus conventional HLA-A2-specific CD8 T cells to long-term [...] Read more.
This study investigated the frequency and peptide specificity of long-lasting HCMV-specific CD8 T cells in a cohort of 120 cytomegalovirus seropositive (HCMV+) healthy carriers with the aim of deciphering the relative contribution of unconventional HLA-E- versus conventional HLA-A2-specific CD8 T cells to long-term T cell memory expansion in HCMV immunity. The presence of HCMV-specific CD8 T cells was investigated by flow cytometry using five MHC/peptide tetramer complexes (HLA-A2/pp65, HLA-A2/IE1 and three different HLA-E/UL40). Here, we report that 50% of HCMV+ healthy individuals possess HCMV-specific CD8 T cells, representing ≥0.1% of total blood CD8 T cells years post-infection. Around a third (30.8%) of individuals possess HLA-A2-restricted (A2pp65 or A2IE1) and an equal proportion (27.5%) possess an HLA-E/UL40 CD8 T response. Concomitant HLA-E- and HLA-A2-reactive CD8 T cells were frequently found, and VMAPRTLIL peptide was the major target. The frequency of HLA-E/VMAPRTLIL among total blood CD8 T cells was significantly higher than the frequency of HLA-A2pp65 T cells (mean values: 5.9% versus 2.3%, p = 0.0354). HLA-EUL40 CD8 T cells display lower TCR avidity but similar levels of CD3 and CD8 coreceptors. In conclusion, HLA-E-restricted CD8 T cells against the VMAPRTLIL UL40 peptide constitute a predominant subset among long-lasting anti-HCMV CD8 T cells. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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13 pages, 3243 KiB  
Article
Application of Digital Holographic Microscopy to Analyze Changes in T-Cell Morphology in Response to Bacterial Challenge
by Kari Lavinia vom Werth, Björn Kemper, Stefanie Kampmeier and Alexander Mellmann
Cells 2023, 12(5), 762; https://doi.org/10.3390/cells12050762 - 27 Feb 2023
Cited by 19 | Viewed by 2526
Abstract
Quantitative phase imaging (QPI) is a non-invasive, label-free technique used to detect aberrant cell morphologies caused by disease, thus providing a useful diagnostic approach. Here, we evaluated the potential of QPI to differentiate specific morphological changes in human primary T-cells exposed to various [...] Read more.
Quantitative phase imaging (QPI) is a non-invasive, label-free technique used to detect aberrant cell morphologies caused by disease, thus providing a useful diagnostic approach. Here, we evaluated the potential of QPI to differentiate specific morphological changes in human primary T-cells exposed to various bacterial species and strains. Cells were challenged with sterile bacterial determinants, i.e., membrane vesicles or culture supernatants, derived from different Gram-positive and Gram-negative bacteria. Timelapse QPI by digital holographic microscopy (DHM) was applied to capture changes in T-cell morphology over time. After numerical reconstruction and image segmentation, we calculated single cell area, circularity and mean phase contrast. Upon bacterial challenge, T-cells underwent rapid morphological changes such as cell shrinkage, alterations of mean phase contrast and loss of cell integrity. Time course and intensity of this response varied between both different species and strains. The strongest effect was observed for treatment with S. aureus-derived culture supernatants that led to complete lysis of the cells. Furthermore, cell shrinkage and loss of circular shape was stronger in Gram-negative than in Gram-positive bacteria. Additionally, T-cell response to bacterial virulence factors was concentration-dependent, as decreases in cellular area and circularity were enhanced with increasing concentrations of bacterial determinants. Our findings clearly indicate that T-cell response to bacterial stress depends on the causative pathogen, and specific morphological alterations can be detected using DHM. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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12 pages, 5017 KiB  
Article
cfDNA Methylation Profiles and T-Cell Differentiation in Women with Endometrial Polyps
by Xiao-Hong Li, Mei-Yin Lu, Jia-Li Niu, Dong-Yan Zhu and Bin Liu
Cells 2022, 11(24), 3989; https://doi.org/10.3390/cells11243989 - 9 Dec 2022
Cited by 2 | Viewed by 2317
Abstract
DNA methylation is a part of the regulatory mechanisms of gene expression, including chromatin remodeling and the activity of microRNAs, which are involved in the regulation of T-cell differentiation and function. However, the role of cfDNA methylation in T-cell differentiation is entirely unknown. [...] Read more.
DNA methylation is a part of the regulatory mechanisms of gene expression, including chromatin remodeling and the activity of microRNAs, which are involved in the regulation of T-cell differentiation and function. However, the role of cfDNA methylation in T-cell differentiation is entirely unknown. In patients with endometrial polyps (EPs), we have found an imbalance of T-cell differentiation and an aberrant cfDNA methylation profile, respectively. In this study, we investigated the relationship between cfDNA methylation profiles and T-cell differentiation in 14 people with EPs and 27 healthy controls. We found that several differentially methylated genes (DMGs) were associated with T-cell differentiation in people with EPs (ITGA2-Naïve CD4, r = −0.560, p = 0.037; CST9-EMRA CD4, r = −0.626, p = 0.017; and ZIM2-CM CD8, r = 0.576, p = 0.031), but not in healthy controls (all p > 0.05). When we combined the patients’ characteristics, we found a significant association between ITGA2 methylation and polyp diameter (r = 0.562, p = 0.036), but this effect was lost when adjusting the level of Naïve CD4 T-cells (r = 0.038, p = 0.903). Moreover, the circulating sex hormone levels were associated with T-cell differentiation (estradiol-Naïve CD4, r = −0.589, p = 0.027), and the cfDNA methylation profile (testosterone-ZIM2, r = −0.656, p = 0.011). In conclusion, this study has established a link between cfDNA methylation profiles and T-cell differentiation among people with EPs, which may contribute to the etiology of EPs. Further functional studies are warranted. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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Graphical abstract

18 pages, 3286 KiB  
Article
Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients
by Sarah Cristina Gozzi-Silva, Luana de Mendonça Oliveira, Ricardo Wesley Alberca, Natalli Zanete Pereira, Fábio Seiti Yoshikawa, Anna Julia Pietrobon, Tatiana Mina Yendo, Milena Mary de Souza Andrade, Yasmim Alefe Leuzzi Ramos, Cyro Alves Brito, Emily Araujo Oliveira, Danielle Rosa Beserra, Raquel Leão Orfali, Valéria Aoki, Alberto Jose da Silva Duarte and Maria Notomi Sato
Cells 2022, 11(21), 3359; https://doi.org/10.3390/cells11213359 - 25 Oct 2022
Cited by 12 | Viewed by 2644
Abstract
COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is [...] Read more.
COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is frequent. However, the profiles of CD4+ and CD8+ T cells regarding cytotoxicity and antiviral factor expression have not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study was to evaluate the phenotypic and functional profile of T lymphocytes in patients with moderate and severe/critical COVID-19. During the pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Notwithstanding lymphopenia, we observed an increase in the expression of CD28, a co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T lymphocytes as well as an increase in the frequency of CD4+ T cells, CD8+ T cells, and NK cells that express the immunological checkpoint protein PD-1 in patients with a severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T cells was already observed at the baseline level and scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T lymphocytes decreased the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed by t-SNE, there were CD4+ T-cytotoxic and CD8+ T with low granzyme production, evidencing their dysfunction in severe/critical conditions. In addition, purified CD8+ T lymphocytes from patients with severe COVID-19 showed increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and, curiously, had reduced expression of TNF-α. The cytotoxic profile of CD4+ T cells may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T cells and CD8+ T cells in the severity of acute COVID-19 infection. Full article
(This article belongs to the Special Issue T Cells: Differentiation and Function in Immunity and Disease)
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