T FH Cells Induced by Vaccination and Following SIV Challenge Support Env-Specific Humoral Immunity in the Rectal-Genital Tract and Circulation of Female Rhesus Macaques.

T follicular helper (T _FH ) cells are pivotal in lymph node (LN) germinal center (GC) B cell affinity maturation. Circulating CXCR5 ⁺ CD4 ⁺ T (cT _FH ) cells have supported memory B cell activation and broadly neutralizing antibodies in HIV controllers. We investigated the contribution of LN SIV-specific T _FH and cT _FH cells to Env-specific humoral immunity in female rhesus macaques following a mucosal Ad5hr-SIV recombinant priming and SIV gp120 intramuscular boosting vaccine regimen and following SIV vaginal challenge. T _FH and B cells were characterized by flow cytometry. B cell help was evaluated in T _FH -B cell co-cultures and by real-time PCR. Vaccination induced Env-specific T _FH and Env-specific memory (ESM) B cells in LNs. LN Env-specific T _FH cells post-priming and GC ESM B cells post-boosting correlated with rectal Env-specific IgA titers, and GC B cells at the same timepoints correlated with vaginal Env-specific IgG titers. Vaccination expanded cT _FH cell responses, including CD25 ⁺ Env-specific cT _FH cells that correlated negatively with vaginal Env-specific IgG titers but positively with rectal Env-specific IgA titers. Although cT _FH cells post-2 ^nd boost positively correlated with viral-loads following SIV challenge, cT _FH cells of SIV-infected and protected macaques supported maturation of circulating B cells into plasma cells and IgA release in co-culture. Additionally, cT _FH cells of naïve macaques promoted upregulation of genes associated with B cell proliferation, BCR engagement, plasma cell maturation, and antibody production, highlighting the role of cT _FH cells in blood B cell maturation. Vaccine-induced LN T _FH and GC B cells supported anti-viral mucosal immunity while cT _FH cells provided B cell help in the periphery during immunization and after SIV challenge. Induction of T _FH responses in blood and secondary lymphoid organs is likely desirable for protective efficacy of HIV vaccines.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Helmold Hait, Hogge, Rahman, Hunegnaw, Mushtaq, Hoang and Robert-Guroff.)