Interferon-γ (IFN-γ)-producing CD4+ T helper-1 (Th1) cells are critical for protection from microbes that infect the phagosomes of myeloid cells. Current understanding of Th1 cell differentiation is based largely on reductionist cell culture experiments. We assessed Th1 cell generation in vivo by studying antigen-specific CD4+ T cells during infection with the phagosomal pathogen Salmonella enterica (Se), or influenza A virus (IAV), for which CD4+ T cells are less important. Both microbes induced T follicular helper (Tfh) and interleukin-12 (IL-12)-independent Th1 cells. During Se infection, however, the Th1 cells subsequently outgrew the Tfh cells via an IL-12-dependent process and formed subsets with increased IFN-γ production, ZEB2-transcription factor-dependent cytotoxicity, and capacity to control Se infection. Our results indicate that many infections induce a module that generates Tfh and poorly differentiated Th1 cells, which is followed in phagosomal infections by an IL-12-dependent Th1 cell amplification module that is critical for pathogen control.
Bibliographical noteFunding Information:
This work was funded by grants from the US National Institutes of Health R01 AI039614 and R01 AI103760 to M.K.J., T32 AI83196 to D.I.K., and T32 HL007062 to P. D. K. and M.F.G. The authors acknowledge Jennifer Walter and Charles Elwood for their help with maintaining mice and Juan Abrahante Llorens for his help with analysis of RNA sequence data.
© 2021 Elsevier Inc.
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