Emerging concepts on T follicular helper cell dynamics in HIV infection

Abstract

Inducing cross-reactive broadly neutralizing antibody (bNAb) responses to HIV through vaccination remains an insurmountable challenge. T follicular helper (TFH) cells are fundamental for the development of antigen-specific antibody responses and therefore crucial for anti-HIV vaccine design. Here, we review recent studies supporting an intricate involvement of TFH cells in HIV pathogenesis and bNAb development during HIV infection. We also examine emerging data suggesting that TFH cell responses may be traceable in peripheral blood, and discuss the implications of these findings in the context of vaccine design and future research in TFH cell immunobiology.

Keywords: HIV; HIV neutralizing antibody; T follicular helper cells; broadly neutralizing antibody; follicular B helper T cell; peripheral blood T follicular helper T cell (pTfh); vaccine.

Figure 1. Development of T_FH cells and the germinal center reaction

(1) Dendritic cells present antigen and activate naïve CD4 T cells via TCR:MHC-II, ICOS-ICOS-L, and CD40:CD40L interactions to initiate the T_FH program. DC- and B cell-derived IL-6 and IL-27 cytokines maintain and reinforce this lineage, leading to upregulation of the T_FH transcription factors Bcl6, cMaf, and CXCR5. (2) Expression of CXCR5 facilitates the migration of pre-T_FH cells toward the T—B cell interphase. Here, cognate pre-T_FH and B cells exchange molecular signals including ICOS:ICOS-L, CD40:CD40L, TCR:MHC-II, and several SLAM receptor family members, as well as several cytokines including the cardinal cytokine IL-21, that reinforce expression of Bcl6 and c-Maf that further increase expression of T_FH surface receptors. B cells simultaneously undergo diverse signals that instruct their maturation pathway: either extrafollicular or GC. (3) Extrafollicular activated B cells then convert to short-lived plasma cells and secrete Ab with or without extrafollicular T_FH help. (4) In the GC, prolonged interactions between GC T_FH and GC B cells further confirm the T_FH lineage commitment, resulting in mutual exchange of survival signals that result in GC maintenance. GC T_FH cells provide a limiting source of antigen for which B cells compete for survival signals based on BCR affinity. Furthermore, here GC T_FH cells instruct GC B cells to phosphorylate and express Activation-induced Deaminase (AID) that mediates SHM, CSR, memory cell and long-lived plasma cell formation.

Figure 2. HIV/SIV-mediated T_FH dysfunction and immunopathogenesis

(a.) HIV/SIV mediated immune activation induces high IL-6 production found within infected lymph nodes. (b.) IL-6 induces expansion of (potentially dysfunctional) T_FH cells expressing high levels of Bcl6 and IL-6Rα. T_FH expansion is further associated with increased numbers of GC B cells. (c.) GC T_FH expansion increases contact with PD-L1-expressing GC B cells, resulting in deregulated GC T_FH cells and inadequate help provisioned to GC B cells, likely by lowering the selection threshold and decreasing IL-21 signaling (and other T_FH cytokines such as IFN γ and IL-10) that lead B cell differentiation into short-lived PC formation and increased polyclonal and HIV/SIV-specific (primarily targeting Gag) IgG production. (d.) Similarly, direct IL-6 signaling may also mediate spontaneous terminal differentiation of memory B cell into plasma cells, resulting in observed decrease of memory B cells in HIV/SIV infection. (e.) High antigenic availability within the lymph node likely also enhances plasma cell survival. (f.) High antigenemia likely also contributes to B cell exhaustion, apoptosis, and the subsequent aberrant B cell phenotypes. (g.) HIV/SIV infection of T_FH cells (enhanced by IL-6) likely maintains the viral reservoir, as infected T_FH cells, may be resistant to apoptosis; this likely constitutes a latent reservoir within a privileged tissue, as HIV/SIV-specific CD8 CTL relatively seldom enters the lymphoid tissue.