T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 6; pp. 1101 - 1111
• Main Authors: Mackay, Laura K., Wynne-Jones, Erica, Freestone, David, Pellicci, Daniel G., Mielke, Lisa A., Newman, Dane M., Braun, Asolina, Masson, Frederick, Kallies, Axel, Belz, Gabrielle T., Carbone, Francis R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2015; Elsevier
• Subjects: Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes - immunology; Down-Regulation; Flow Cytometry; Gene Expression Regulation - immunology; Immunologic Memory - immunology; Interleukin-15 - immunology; Life Sciences; Lymphocyte Activation - immunology; Mice; Mice, Knockout; peripheral immunity; Polymerase Chain Reaction; T-Box Domain Proteins - immunology; T-box transcription factors; T-Lymphocyte Subsets - immunology; TGF-β; Tissue-resident memory T cells; Transforming Growth Factor beta - immunology; T-box transcription factors; TGF-β; Tissue-resident memory T cells; peripheral immunity
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.11.008

Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8+CD103+ Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8+CD103+ Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8+CD103+ Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8+CD103+ Trm cell development and survival. •CD8+CD103+ Trm cells protect against infection in the absence of circulating memory•T-box transcription factor downregulation drives CD8+CD103+ Trm cell development•TGF-β and the T-box transcription factors show reciprocal downregulation•Residual T-bet expression is required for IL-15-mediated CD8+CD103+ Trm cell survival Molecular events that regulate Trm cell formation remain poorly defined. Mackay and colleagues demonstrate that a complex interplay between Eomes and T-bet underpins CD8+CD103+ Trm cell formation. Although both T-box transcription factors must be downregulated, Eomes must be completely extinguished, whereas residual T-bet expression is essential for IL-15-mediated long-term survival.