The Peptide Specificity of the Endogenous T Follicular Helper Cell Repertoire Generated after Protein Immunization
Sant AJ (2012) The Peptide Specificity of the Endogenous T Follicular Helper Cell Repertoire Generated after Protein Immunization. PLoS
ONE 7(10): e46952. doi:10.1371/journal.pone.0046952
The Peptide Specificity of the Endogenous T Follicular Helper Cell Repertoire Generated after Protein Immunization
Scott A. Leddon 0
Andrea J. Sant 0
George Kassiotis, MRC National Institute for Medical Research, United Kingdom
0 David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center , Rochester, New York , United States of America
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.
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Funding: This work was supported by grants HHSN27220201200005C, HHSN266200700008C and R01AI51542, and 5T32AI007285 from the National Institutes of
Health (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
The generation of a high-affinity class-switched antibody
response is the most common benchmark for successful
vaccination (reviewed in [1,2]). T follicular helper (Tfh) cells are an
indispensable and limiting factor during the germinal center
response [35] that gives rise to both memory B cells and
longlived plasma cells, which in turn generate and sustain protective
antibody responses (reviewed [6,7]). While much progress has
been made in understanding the development and function of the
Tfh lineage over the past several years, questions about the
diversity and peptide specificity of the Tfh response generated after
immunization remain unaddressed.
After immunization or infection, nave T cells are initially primed
through interaction with antigen-bearing dendritic cells (DC) in the
T cell zone. 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 also into the interfollicular zones
[810]. Here, they have an opportunity to interact with
peptidepresenting B cells prior to entry into germinal centers. 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 [1214], several experimental systems in which B
cells are either absent [1417], deficient in MHC class II gene
expression [13], or are incapable of sustained interactions with T
cells [1820] 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 [2127]), 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].
Because cognate interactions are required for T cell priming and
Tfh differentiation, the sets of peptides presented by DC and B cells
are likely to influence the specificity of Tfh cells generated during an
immune response. Differences in how B cells and DC access,
acquire, process, and edit antigen could result in these cell types
presenting distinct repertoires of peptide-MHC class II complexes
[2933] (reviewed in [3439]). If B cells are unable to present
epitopes that are presented (...truncated)