The receptor repertoire and functional profile of follicular T cells in HIV-infected lymph nodes

Follicular helper CD4(+)T cells (T-FH) play an integral role in promoting B cell differentiation and affinity maturation. Whereas T-FH cell frequencies are increased in lymph nodes (LNs) from individuals infected with HIV, humoral immunity remains impaired during chronic HIV infection. Whether HIV inhibits T-FH responses in LNs remains unclear. Advances in this area have been limited by the difficulty of accessing human lymphoid tissues. Here, we combined high-dimensional mass cytometry with T cell receptor repertoire sequencing to interrogate the composition of T-FH cells in primary human LNs. We found evidence for intact antigen-driven clonal expansion of T-FH cells and selective utilization of specific complementarity-determining region 3 (CDR3) motifs during chronic HIV infection, but the resulting T-FH cells acquired an activation-related T-FH cell signature characterized by interleukin-21 (IL-21) dominance. These IL-21(+) T-FH cells contained an oligoclonal HIV-reactive population that preferentially accumulated in patients with severe HIV infection and was associated with aberrant B cell distribution in the same LN. These data indicate that T-FH cells remain capable of responding to HIV antigens during chronic HIV infection but become functionally skewed and oligoclonally restricted under persistent antigen stimulation.