Transcriptional downregulation of S1pr1 is required for establishment of resident memory CD8+ T cells

By Cara N. Skon, June-Yong Lee, K. Anderson, D. Masopust, K. Hogquist, S. Jameson. Nature Immunology, 2013

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Cell-mediated immunity critically depends on the localization of lymphocytes at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells (TRM cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of TRM cells is unknown. We found that CD8+ TRM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P1, a receptor for sphingosine 1-phosphate). Forced expression of S1P1 prevented the establishment of TRM cells. Cytokines that induced a TRM cell phenotype (including transforming growth factor-β (TGF-β), interleukin 33 (IL-33) and tumor-necrosis factor) elicited downregulation of KLF2 expression in a pathway dependent on phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt, which suggested environmental regulation. Hence, regulation of KLF2 and S1P1 provides a switch that dictates whether CD8+ T cells commit to recirculating or tissue-resident memory populations.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/c157f0989e55d40ef85533be5c1b3ea2c9f72e99

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Citations in the corpus

Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites (2017, background): “The genes differentially expressed by human CD69+ and CD69 TEM cells (Figure 2C) included key molecules associated with mouse CD8+ TRMs from infection models (Mackay et al., 2013, 2016; Skon et al., 2013; Wakim et al., 2012).”
CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin (2017, neutral): “CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues (Mackay et al., 2015; Skon et al., 2013).”
Quantifying memory CD8 T cells reveals regionalization of immunosurveillance (2015, background): “Maintenance of CD69 TRM could be mediated by alternative means such as downregulation of KLF2-dependent S1P receptors (Skon et al., 2013).”
Chemokines and chemokine receptors: positioning cells for host defense and immunity. (2014, background): “Once in the efferent lymph and/or the blood, S1P1 is desensitized by sustained S1P signaling and CCR7 is upregulated again, allowing the cycle to begin anew (56).”
Tissue-Resident Memory T Cells (2014, background): “When S1PR1 is forcibly expressed on CD8+ T cells, Trm cells are reduced in NLTs (Skon et al., 2013).”
Human T cell development, localization, and function throughout life (2018, background): “, 2016), shown to be required for Trm cells formation in mice (Skon et al., 2013).”