Smad4 Promotes Differentiation of Effector and Circulating Memory CD8 T Cells but Is Dispensable for Tissue-Resident Memory CD8 T Cells


Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGF-β promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-β but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-β receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity.

Document Type


Publication Date


Notes/Citation Information

Published in The Journal of Immunology, v. 194, no. 5, p. 2407-2414.

Copyright © 2015 by The American Association of Immunologists, Inc.

Digital Object Identifier (DOI)


Funding Information

This work was supported by National Institutes of Health Grant AI056172.

Related Content

The online version of this article contains supplemental material.