title: Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells.
abstract: 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.
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032;
authors: Yinghong
authors: Y
authors: Hu
authors: Georgia State University, Atlanta, GA 30302;
authors: Young-Tae
authors: YT
authors: Lee
authors: Yale School of Medicine, New Haven, CT 06520; and.
authors: Susan M
authors: SM
authors: Kaech
authors: University of Kentucky College of Medicine, Lexington, KY 40536.
authors: Beth
authors: B
authors: Garvy
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032; lcauley@UCHC.edu.
authors: Linda S
authors: LS
authors: Cauley
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology*; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology; D018183:Transplantation Chimera
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; C091367:alpha E integrins
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