IL-27 induces a cytotoxic state in CD4+ T cells distinct from the Th1 lineage
- 1La Jolla Institute for Immunlogy
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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BibTeX
@misc{matias2026il27,
title = {{IL-27 induces a cytotoxic state in CD4+ T cells distinct from the Th1 lineage}},
author = {M. I. Matias and R. Marrocco and K. Magro and L. D. Sanchez Solis and S. Figueroa Buezo and L. Laura Hinojosa-Gonzalez and M. Jabou and H. Lu and E. Ehinger and G. Ascui and Y. Zheng and F. AY and C. A. Benedict and S. A. Myers},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.746061},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.746061v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - IL-27 induces a cytotoxic state in CD4+ T cells distinct from the Th1 lineage
AU - M. I. Matias
AU - R. Marrocco
AU - K. Magro
AU - L. D. Sanchez Solis
AU - S. Figueroa Buezo
AU - L. Laura Hinojosa-Gonzalez
AU - M. Jabou
AU - H. Lu
AU - E. Ehinger
AU - G. Ascui
AU - Y. Zheng
AU - F. AY
AU - C. A. Benedict
AU - S. A. Myers
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.746061
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.746061v1
AB - 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.
ER -