CD4 T cell epitope specificity determines follicular versus non-follicular helper differentiation in the polyclonal response to influenza infection or vaccination

Abstract

Follicular helper T cells (Tfh) are essential for B cell production of high-affinity, class-switched antibodies. Much interest in Tfh development focuses on the priming environment of CD4 T cells. Here we explored the role that peptide specificity plays in the partitioning of the polyclonal CD4 T cell repertoire between Tfh and NonTfh lineages during the response to influenza. Surprisingly, we found that CD4 T cells specific for different epitopes exhibited distinct tendencies to segregate into Tfh or NonTfh. To alter the microenvironment and abundance, viral antigens were introduced as purified recombinant proteins in adjuvant as native proteins. Also, the most prototypical epitopes were expressed in a completely foreign protein. In many cases, the epitope-specific response patterns of Tfh vs. NonTfh persisted. The functional TcR avidity of only a subset of epitope-specific cells correlated with the tendency to drive a Tfh response. Thus, we conclude that in a polyclonal CD4 T cell repertoire, features of TcR-peptide:MHC class II complex have a strong deterministic influence on the ability of CD4 T cells to become a Tfh or a NonTfh. Our data is most consistent with at least 2 checkpoints of Tfh selection that include both TcR affinity and B cell presentation.

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

“…While these processes are critical in early Tfh differentiation, nascent Tfh cells require functional B cell interactions to complete Tfh commitment 37,38 . Finally, the T cell receptor (TCR) of the naïve cell may also shape the differentiation process, given that properties of TCR binding and signaling have been demonstrated to drive Tfh differentiation 39–44 .…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Second, is Tfh cell avidity important? A recent study of the influenza‐virus‐specific CD4 + T‐cell response indicated that T cells responding to different epitopes exhibited distinct tendencies to develop into Tfh cells, with those exhibiting a higher functional avidity being more likely to become Tfh cells203; but whether Tfh cells of higher avidity also mediate superior help for B cells is not clear. No associations have been reported between HLA class II type and bnAb induction during HIV‐1 infection that may support a role for T‐cell responses of particular specificity favoring or disfavoring bnAb induction47; but as many CD4 T‐cell epitopes are promiscuously presented by multiple HLA class II alleles,204 this does not preclude a relationship between epitope recognition and help for bnAb induction.…”

“…Second, is Tfh cell avidity important? A recent study of the influenza-virus-specific CD4 + T-cell response indicated that T cells responding to different epitopes exhibited distinct tendencies to develop into Tfh cells, with those exhibiting a higher functional avidity being more likely to become Tfh cells 203 ; but whether Tfh cells of higher avidity also mediate superior help for B cells is not clear.…”

Signals that drive T follicular helper cell formation

“…Although high‐affinity CD4 + T‐cell clones and T‐cell receptors (TCR) with the strongest peptide–MHCII binding show skewed differentiation into Tfh cells, this is most likely due to increased clonal expansion in response to high‐affinity antigens . It has been suggested that although antigen affinity does not correlate with partitioning to Tfh cell fate, different peptide epitopes may dictate T helper type 1 (Th1) versus Tfh cell differentiation . Intriguingly, single cell transfer demonstrated that individual polyclonal T cells specific for a single peptide tend to produce progeny with a specific balance of Th1 and Tfh cells .…”

“…8,9 It has been suggested that although antigen affinity does not correlate with partitioning to Tfh cell fate, different peptide epitopes may dictate T helper type 1 (Th1) versus Tfh cell differentiation. 10 Intriguingly, single cell transfer demonstrated that individual polyclonal T cells specific for a single peptide tend to produce progeny with a specific balance of Th1 and Tfh cells. 11 This divergence was due to enhanced Tfh differentiation with increased aggregate dwell time (the half-life for which a TCR productively binds to its cognate pMHCII ligand).…”