Abstract
Transforming growth factor β (TGFβ) is a morphogenic protein that augments antiviral immunity by altering the functional properties of pathogen-specific memory CD8 T cells. During infection TGFβ inhibits formation of effector (TEFF) and central memory CD8 T cells (TCM), while encouraging tissue-resident memory CD8 T cells (TRM) to settle in peripheral tissues. SMAD proteins are signaling intermediates that are used by members of the TGF cytokine family to modify gene expression. For this study, RNA-sequencing was used to explore how regulation via SMAD4 alters the transcriptional profile of antiviral CTLs during infection. We show that SMAD4 and TGFβ cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissue. The target genes include multiple homing receptors (CD103, KLRG1 and CD62L) and transcription factors (Hobit and EOMES) that support memory formation. While TGFβ uses a canonical SMAD-dependent signaling pathway to induce CD103 expression on TRM cells, an alternative SMAD4-dependent mechanism is required for formation of TEFF and TCM cells in the circulation.
Graphical abstract TGFβ and SMAD4 modulate gene expression in reciprocal directions during differentiation of antiviral CTLs.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This paper has been updated to address reviewer concerns. Updates include new data.
