Abstract
T follicular helper (Tfh) cells potentiate high-affinity, class-switched antibody responses, the predominant correlate of protection from vaccines. Despite intense interest in understanding both the generation and effector functions of this lineage, little is known about the epitope specificity of Tfh cells generated during polyclonal responses. To date, studies of peptide-specific Tfh cells have relied on either the transfer of TcR transgenic cells or use of peptide∶MHC class II tetramers and antibodies to stain TcR and follow limited peptide specificities. In order to comprehensively evaluate polyclonal responses generated from the natural endogenous TcR repertoire, we developed a sorting strategy to separate Tfh cells from non-Tfh cells and found that their epitope-specific responses could be tracked with cytokine-specific ELISPOT assays. The immunodominance hierarchies of Tfh and non-Tfh cells generated in response to immunization with several unrelated protein antigens were remarkably similar. Additionally, increasing the kinetic stability of peptide-MHC class II complexes enhanced the priming of both Tfh and conventional CD4 T cells. These findings may provide us with a strategy to rationally and selectively modulate epitope-specific Tfh responses. By understanding the parameters that control epitope-specific priming, vaccines may be tailored to enhance or focus Tfh responses to facilitate optimal B cell responses.
Highlights
The generation of a high-affinity class-switched antibody response is the most common benchmark for successful vaccination
The studies described here indicate that T follicular helper (Tfh) cells within the lymph node are robust producers of many cytokines, peptide-specific responses can be evaluated with diverse cytokine-specific ELISPOT assays, and the immunodominance hierarchy of the peptide-specific responses within the Tfh and non-Tfh subsets are remarkably similar
We found that the immunodominance hierarchies of Tfh and non-Tfh populations were similar at the peak of the immune response, and persisted for over 25 days post immunization
Summary
The generation of a high-affinity class-switched antibody response is the most common benchmark for successful vaccination (reviewed in [1,2]). As a consequence of interactions with DC, a fraction of the activated T cells gain expression of CXCR5 and BCL6 and decrease CCR7 expression This change in chemokine receptor expression allows for migration of these T cells from the T cell zone to the border of the B cell zone and into the interfollicular zones [8,9,10]. Cognate antigen presentation by germinal center B cells is required to recruit T cell help for class-switching, affinity maturation, and differentiation into memory and long-lived plasma cells (reviewed in [11]). While it is clear that DC are necessary and sufficient for the initiation of the Tfh response [12,13,14], several experimental systems in which B cells are either absent [14,15,16,17], deficient in MHC class II gene expression [13], or are incapable of sustained interactions with T cells [18,19,20] have shown that B cells and B cell antigen presentation are required for sustaining the Tfh response beyond the first few days of the immune response (reviewed in [21,22,23,24,25,26,27]), accumulation of Tfh cells within the B cell follicles, and for Tfh cells to express high levels of the effector molecules PD-1 and IL-21 [12,28]
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