Naive CD4+ T lymphocytes differentiate into various Th cell subsets following TCR binding to microbial peptide:MHC class II (p:MHCII) complexes on dendritic cells (DCs). The affinity of the TCR interaction with p:MHCII plays a role in Th differentiation by mechanisms that are not completely understood. We found that low-affinity TCRs biased mouse naive T cells to become T follicular helper (Tfh) cells, whereas higher-affinity TCRs promoted the formation of Th1 or Th17 cells. We explored the basis for this phenomenon by focusing on IL-2R signaling, which is known to promote Th1 and suppress Tfh cell differentiation. SIRP+ DCs produce abundant p:MHCII complexes and consume IL-2, whereas XCR1+ DCs weakly produce p:MHCII but do not consume IL-2. We found no evidence, however, of preferential interactions between Th1 cell–prone, high-affinity T cells and XCR1+ DCs or Tfh cell–prone, low-affinity T cells and SIRP+ DCs postinfection with bacteria expressing the peptide of interest. Rather, high-affinity T cells sustained IL-2R expression longer and expressed two novel Th cell differentiation regulators, Eef1e1 and Gbp2, to a higher level than low-affinity T cells. These results suggest that TCR affinity does not influence Th cell differentiation by biasing T cell interactions with IL-2–consuming DCs, but instead, directly regulates genes in naive T cells that control the differentiation process.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants R01 AI039614 and P01 AI35296 (to M.K.J.), T32 AI083196 and T32 AI007313 (to D.I.K.), and R01 AI106791 and P01 AI35296 (to B.T.F.). We thank J. Walter, C. Ellwood, the University of Minnesota Center for Immunology Imaging Core, the University of Minnesota Imaging Centers, and the University of Minnesota Flow Cytometry Resource for technical assistance; D. F. Voytas and J. J. Belanto for helping generate the CRISPR/Cas9 system; and M. Y. Gerner for suggestions on histo-cytometry.
This work was supported by National Institutes of Health Grants R01 AI039614 and P01 AI35296 (to M.K.J.), T32 AI083196 and T32 AI007313 (to D.I.K.), and R01 AI106791 and P01 AI35296 (to B.T.F.).