Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions

A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21+CD4+ T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21+CD4+ T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses. •Circulating IL-21+CD4+ T cells are transcriptionally and phenotypically pTfh cells•pTfh cells maintained phenotype and function in culture•Env- or Gag-specific pTfh cells elicited differential quality of help to B cells•Vaccine-induced pTfh cells were highest in the moderately efficacious RV144 trial T follicular helper (Tfh) cells are pivotal for antibody induction. Streeck and colleagues show that HIV-specific Tfh cells circulating in the periphery can be identified by secretion of IL-21 with helper qualities dependent on protein specificity and are found at increased numbers in the moderately protective HIV vaccine trial (RV144).