Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. Ethics Statements
2.3. PBMC Isolation
2.4. Induction of GZMB+ B Cells Ex Vivo
2.5. Cell Multiplexing and Single-Cell RNA Sequencing
2.6. scRNAseq Analysis
2.7. Biopsy Immunofluorescence Staining
3. Results
3.1. Clinical Characteristics of the Patients
3.2. Natural GZMB+ B Cells Display a Differentiated B Cell Profile Enriched in Specific Genes Associated with NK Cells and Regulatory Functions
3.3. Natural GZMB+B Cells Are Highly Differentiated B Cells That Follow a Specific Trajectory Distinct from That of Conventional Memory B Cells, with the KLF13 Gene Overexpressed Throughout This Trajectory
3.4. In General, GZMB+ B Cells from Tolerant Patients Exhibit a Specific Transcriptomic Profile Associated with a Decrease in the Expression of HLA Molecules, Apoptosis, and the Inflammatory Response
3.5. Ex-Vivo-Induced GZMB+ B Cells Share a “Regulatory” Signature with Natural GZMB+ B Cells in Tolerant Patients
3.6. Natural GZMB+ B Cells from Tolerant Patients Interact Strongly with Peripheral Immune Cells
3.7. Under Inflammatory Conditions, GZMB+ B Cells Can Infiltrate Kidney Allografts
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
GZMB+ B cells: | Granzyme B positive B cells with regulatory properties. |
Induced GZMB+ B cells: | GZMB+ B cells generated according to the in vitro protocol described in Chesneau et al. [19]. |
Natural GZMB+ B cells: | B cells from donor’s blood or biopsies expressing GZMB without any restimulation in vitro. |
GZMB− B cells: | B cells used to determine the characteristics of GZMB+ B cells. For the dataset generated after in vitro induction, GZMB− B cells correspond to the conditions that did not receive any stimulation (i.e., total resting B cells after 3 days), as GZMB expression is transient. |
TOL: | Patients with no immunosuppression for at least one year and with stable creatinine < 150 mmol/L and proteinuria < 1 g/24. |
STA: | Patients with stable graft function (creatinine < 150 mmol/L and proteinuria < 0.2 g/g creatinine) for at least 3 years under standard immunosuppression (calcineurin inhibitors [CNIs], antimetabolite ± corticosteroids). |
ABMR: | Patients with histology-proven antibody-mediated rejection. |
DEG: | Differentially expressed gene. |
Appendix A
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STA (n = 4) | ABMR (n = 5) | TOL (n = 4) | |
---|---|---|---|
Sex (M/F) | 3/1 | 2/3 | 3/1 |
Age at the time of analysis (years) | 46.25 ± 17 | 55.4 ± 4 | 45.75 ± 19.1 |
Donor (LD/NLD) | 0/4 | 1/4 | 2/2 |
Time post-transplantation (days) | 1056 ± 1381 | 2178 ± 2783 | 6891 ± 3709 |
Creatinemia (μMol) | 85.25 ± 23.01 | 159.6 ± 42.20 | 126.25 ± 52.81 |
Proteinuria (g/g) | 0 ± 0 | 0.405 ± 0.276 | 0.05 ± 0.01 |
Mismatched HLA * | 4/5/5/5 | 2/4/2/1/3 | 4/3/0/0 |
Immunosuppression at sampling ** | 4 | 5 | 0 |
CNIs | 4 | 5 | 0 |
Steroids | 2 | 5 | 0 |
Antiproliferative | 4 | 4 | 0 |
Sender B Cell Cluster | Ligand-Receptor Pairs | Target Cells |
---|---|---|
B cell Cluster 0 (GZMB−) | / | / |
B cell Cluster 1 (GZMB−) | RPS19-C5AR1 | Mono |
B cell Cluster 2 (GZMB−) | HLA-DMA-CD4/HLA-DMA-CD74/HLA-DPB1-CD4/HLA-DRB1-CD37/HLA-DRB1-CD53/HLA-DRB1-CD81/HLA-DRB1-CD82 HLA-DQA1-CD4/SELL-SELPLG/CLEC2D-KLRB1/HLA-DQB1-CD4/HLA-DRA-CD4/HLA-DRA-CD37/HLA-DRA-CD53/HLA-DRA-CD63/HLA-DRA-CD81/HLA-DRA-CD82/HLA-DMB-CD4/HLA-DMB-CD74 | CD4 T/CD8 T/NK/Mono/B/DC |
B cell Cluster 3 (GZMB+) | CLEC2B-KLRF1/CALR-TAP1/CALR-TAP2/CALR-LRP1/TYROBP-TREM1/TYROBP-KLRD1/HLA-F-CD8A/HLA-F-LILRB1/HLA-F-LILRB2/CD99-CD99/HSP90B1-LRP1/ITGB2-ICAM1/ITGB2-ICAM3/ITGB2-CD82/ITGB2-CD226/B2M-TAP1/B2M-TAP2/B2M-LRP1/B2M-LILRB1/CD7-ADAM15/GZMB-IGF2R/GZMB-MCL1/HLA-B-CD8A/HLA-B-LILRB1/HLA-B-LILRB2/HLA-B-KLRD1/HMGB1-TLR2/HMGB1-TLR4/HMGB1-CXCR4/HMGB1-CD163/HLA-E-CD8A/HLA-E-KLRD1/CD2-CD53/ANXA1-FPR1/TGFB1-TGFBR1/TGFB1-TGFBR2/TGFB1-TGFBR3/TGFB1-APP/TGFB1-ITGB1/HLA-A-CD8A/HLA-A-LILRB1/HLA-A-LILRB2/HLA-A-KLRD1/HLA-A-APLP2/HLA-C-LILRB1/HLA-C-LILRB2/PTPRC-CD4/PTPRC-CD247/CD47-SIRPA/CCL4-CCR1/CCL5-CCR1 | CD4 T/CD8 T/NK/Mono/B/DC |
B cell Cluster 4 (GZMB−) | S100A8-CD36/S100A8-CD68/S100A8-CD69/S100A8-ITGB2 | CD4 T/CD8 T/NK/Mono/B/DC |
B cell Cluster 5 (GZMB−) | LYZ-ITGAL/S100A9-CD36/S100A9-CD68/S100A9-ITGB2/S100A9-TLR4/CD48-CD2 | CD4 T/CD8 T/NK/Mono/B/DC |
General expression | LGALS1-CD69/LGALS1-ITGB1/LGALS1-PTPRC | CD4 T/CD8 T/NK/Mono/B/DC |
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Sailliet, N.; Dupuy, A.; Brinas, F.; Renaudin, K.; Colas, L.; Kerleau, C.; Nguyen, T.-V.-H.; Fourgeux, C.; Poschmann, J.; Gosset, C.; et al. Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells. Cells 2024, 13, 1287. https://doi.org/10.3390/cells13151287
Sailliet N, Dupuy A, Brinas F, Renaudin K, Colas L, Kerleau C, Nguyen T-V-H, Fourgeux C, Poschmann J, Gosset C, et al. Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells. Cells. 2024; 13(15):1287. https://doi.org/10.3390/cells13151287
Chicago/Turabian StyleSailliet, Nicolas, Amandine Dupuy, François Brinas, Karine Renaudin, Luc Colas, Clarisse Kerleau, Thi-Van-Ha Nguyen, Cynthia Fourgeux, Jérémie Poschmann, Clément Gosset, and et al. 2024. "Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells" Cells 13, no. 15: 1287. https://doi.org/10.3390/cells13151287
APA StyleSailliet, N., Dupuy, A., Brinas, F., Renaudin, K., Colas, L., Kerleau, C., Nguyen, T.-V.-H., Fourgeux, C., Poschmann, J., Gosset, C., Giral, M., Degauque, N., Mai, H. L., Danger, R., & Brouard, S., on behalf of the DIVAT Consortium. (2024). Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells. Cells, 13(15), 1287. https://doi.org/10.3390/cells13151287