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.