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.

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

doi:10.3389/fimmu.2020.608003

Mohammad Arif Rahman, Zuena Mushtaq + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2020.608003

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Abstract

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

Highlights

The development of a safe and effective HIV-1 vaccine remains a critically important global health priority
To determine whether the vaccine regimen elicited lymph node (LN) T follicular helper (TFH) cell responses in the rhesus macaques, after gating out Foxp3+ T cells for exclusion of T follicular regulatory (TFR) cells, total LN TFH cells were identified as PD-1+ CXCR5+ CD4+ T cells
Functional cross-talk between TFH cells and B cell populations in secondary lymphoid organs is critical for germinal center (GC) expansion and clonal selection of antigen-specific long-lived plasma cells (PCs) and memory B cells with higher antibody specificity [85,86,87,88]

Summary

Introduction

The development of a safe and effective HIV-1 vaccine remains a critically important global health priority. To date HIV-1 vaccine candidates aimed at eliciting cellular and/or humoral responses have failed to provide significant protection [1]. Antibody production during vaccination and infection is shaped by T follicular helper (TFH) cells, which are a subset of CD4+ T cells specialized in promoting B cell expansion and maturation in B cell follicles and germinal centers (GCs) of secondary lymphoid organs [5]. Several studies have shown that TFH cells play a crucial role in development of broadly neutralizing antibodies (bNAbs) in HIV infected patients [8,9,10,11,12]. TFH cell expansion in lymph nodes (LNs) of rhesus macaques has been associated with development of bNAbs against the HIV envelope during SHIV infection [13]

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