Lymph node and circulating TFH cells support SIV-specific antibody responses in peripheral blood and genital tract of vaccinated female rhesus macaques

Abstract

Abstract TFH cells are critical for Ag-specific B cell selection in germinal centers (GCs). Circulating blood CXCR5+ CD4+ T cells (cTFH) were implicated in development of broadly neutralizing antibodies in HIV+ patients. We asked if an SIV vaccine regimen could induce GC TFH and cTFH cells that supported anti-SIV humoral immunity. Female rhesus macaques (RM) were primed twice mucosally with replicating Ad5hr-SIV recombinants (wks0&13) and boosted twice intramuscularly with SIVgp120 proteins (wks26&38). Blood, lymph nodes (LN), bone marrow (BM), vaginal and rectal swabs were collected pre-vaccination, post-2nd prime and post-2nd boost for TFH and B cell assessment. Total TFH, and Env-specific GC TFH cells and Env-specific memory (ESM) B cells were seen at wk38+3d, suggesting vaccine-mediated GC maturation. Env-specific LN TFH cells and GC B cells at wk13+3d correlated respectively with Env-specific rectal IgA and vaginal IgG titers at wk16. GC B cells and ESM B cells at wk38+3d correlated with Env-specific vaginal IgG and rectal IgA titers at wk41 respectively, indicating early GC formation contributed to SIV-specific immunity in the female genital tract (FGT). Env-specific cTFH cells peaked post-boosting and positively correlated with Env-specific IgA and IgG secreting plasmablasts and plasma cells in BM and rectal IgA titers. cTFH cells induced CD38 and CD138 upregulation in autologous B cells and supported IgA secretion in cocultures compared to B cells cultured alone or with non-cTFH cells. Our data indicate the prime/boost regimen induced GC TFH and cTFH cells, enabling robust anti-SIV T-cell-dependent mucosal and systemic B cell responses. Both LN and circulating TFH cells may play pivotal roles in FGT protective humoral immunity.