Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells

J Immunol. 2015 Mar 1;194(5):2407-14. doi: 10.4049/jimmunol.1402369. Epub 2015 Jan 30.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation
  • Cell Lineage / immunology*
  • Gene Expression Regulation
  • Immunologic Memory*
  • Influenza A virus / immunology
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / immunology
  • Lung / drug effects
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • Signal Transduction
  • Smad4 Protein / deficiency
  • Smad4 Protein / genetics
  • Smad4 Protein / immunology*
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / pharmacology
  • Transplantation Chimera


  • Antigens, CD
  • Integrin alpha Chains
  • Receptors, Transforming Growth Factor beta
  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta
  • alpha E integrins