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Mapping the extent of heterogeneity of human CCR5+ CD4 T-cells in peripheral blood and lymph nodes

Zaunders, J., Munier, C.M.L., McGuire, H. et al.

Background: CD4 T-cells that express the chemokine receptor, CCR5, are the most important target of HIV-1 infection, but their functions, phenotypes and anatomical locations are poorly understood. We aimed to use multiparameter flow cytometry to better define the full breadth of these cells.

Methods: High-parameter fluorescence flow and mass cytometry were optimized to analyse subsets of CCR5+ memory CD4 T-cells, including CD25CD127 Tregs, CXCR3+CCR6- Th1, CCR6+CD161+CXCR3- Th17, integrins α4+ß7+ gut-homing, CCR4+ skin-homing, CD62L+ lymph node-homing, CD38+HLA-DR+ activated cells, and CD27-CD28- cytotoxic T lymphocytes (CTL), in a total of 22 samples of peripheral blood, ultrasound-guided fine needle biopsies of lymph nodes and excised tonsils. CCR5+ antigen-specific CD4 T-cells were studied using the OX40 flow-based assay.

Results: 10-20% of CCR5+ memory CD4 T-cells were Tregs, 10-30% were gut-homing, 10-30% were skin-homing, 20-40% were lymph node-homing, 20-50% were Th1 and 20-40% were Th17 cells. Up to 30% were CTL in CMV-seropositive donors, including cells that were either CCR5Granzyme K+ or CCR5Granzyme B+. When all possible phenotypes were exhaustively analysed, > 150 different functional and trafficking subsets of CCR5+ CD4 T-cells were seen. Also, a small population of resident CD69+Granzyme K+CCR5+ CD4 T-cells was found in lymphoid tissues. CMV- and M tuberculosis-specific CD4 T-cells were predominantly CCR5+.

Conclusions: These results reveal for the first time the prodigious heterogeneity of function and trafficking of CCR5+ CD4 T-cells in blood and in lymphoid tissue, with significant implications for rational approaches to prophylaxis for HIV-1 infection and for purging of the HIV-1 reservoir in those subjects already infected.

Citation

Zaunders, J., Munier, C.M.L., McGuire, H. et al. "Mapping the extent of heterogeneity of human CCR5+ CD4 T-cells in peripheral blood and lymph nodes" AIDS (2020): DOI: 10.1097/QAD.0000000000002503