IL-27 induces a cytotoxic state in CD4+ T cells distinct from the Th1 lineage
Matias, M. I.; Marrocco, R.; Magro, K.; Sanchez Solis, L. D.; Figueroa Buezo, S.; Laura Hinojosa-Gonzalez, L.; Jabou, M.; Lu, H.; Ehinger, E.; Ascui, G.; Zheng, Y.; AY, F.; Benedict, C. A.; Myers, S. A.
Show abstract
CD4+ cytotoxic T lymphocytes (CD4-CTLs) are understudied immune mediators with ambiguous origins. Despite expressing RUNX3, granzyme B (GZMB), and perforin (PRF1), CD4-CTLs are frequently classified as Th1 extensions due to shared interferon-{gamma} (IFN{gamma}) and T-BET expression. Here, we identify interleukin-27 (IL-27) as a independent inducer of a distinct CD4-CTL program. Proteomics reveals that while IL-27-polarized CD4+ T cells share protein signatures with conventional Th1s and CD8+ T cells, they possess a unique molecular landscape with re-wired cytokine signaling networks and a potent cytotoxic protein profile. Mechanistically, this program requires STAT1 and T-BET but operates independently of the autocrine IFN{gamma} feedback that sustains Th1 cells. During acute murine cytomegalovirus infection, IL-27 receptor signaling contributes to CD4-CTL differentiation in vivo, as its loss leads to reduced GZMB expression and skews CD4+ T cells toward IFN{gamma}+ and FOXP3+ subsets. Together, these findings establish IL-27 as a potent and previously unappreciated inducer of CD4-CTLs.
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