AUTHOR=Helmold Hait Sabrina , Hogge Christopher James , Rahman Mohammad Arif , Hunegnaw Ruth , Mushtaq Zuena , Hoang Tanya , Robert-Guroff Marjorie 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.608003

DOI=10.3389/fimmu.2020.608003

ISSN=1664-3224

ABSTRACT=<p>T follicular helper (T<sub>FH</sub>) cells are pivotal in lymph node (LN) germinal center (GC) B cell affinity maturation. Circulating CXCR5<sup>+</sup> CD4<sup>+</sup> T (cT<sub>FH</sub>) cells have supported memory B cell activation and broadly neutralizing antibodies in HIV controllers. We investigated the contribution of LN SIV-specific T<sub>FH</sub> and cT<sub>FH</sub> 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<sub>FH</sub> and B cells were characterized by flow cytometry. B cell help was evaluated in T<sub>FH</sub>-B cell co-cultures and by real-time PCR. Vaccination induced Env-specific T<sub>FH</sub> and Env-specific memory (ESM) B cells in LNs. LN Env-specific T<sub>FH</sub> 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<sub>FH</sub> cell responses, including CD25<sup>+</sup> Env-specific cT<sub>FH</sub> cells that correlated negatively with vaginal Env-specific IgG titers but positively with rectal Env-specific IgA titers. Although cT<sub>FH</sub> cells post-2<sup>nd</sup> boost positively correlated with viral-loads following SIV challenge, cT<sub>FH</sub> cells of SIV-infected and protected macaques supported maturation of circulating B cells into plasma cells and IgA release in co-culture. Additionally, cT<sub>FH</sub> 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<sub>FH</sub> cells in blood B cell maturation. Vaccine-induced LN T<sub>FH</sub> and GC B cells supported anti-viral mucosal immunity while cT<sub>FH</sub> cells provided B cell help in the periphery during immunization and after SIV challenge. Induction of T<sub>FH</sub> responses in blood and secondary lymphoid organs is likely desirable for protective efficacy of HIV vaccines.</p>