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

Abstract

Cell-mediated immunity critically depends on lymphocyte localization at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells; TRM) are embedded in non-lymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for TRM establishment is unknown. We report that CD8+ TRM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (encoding sphingosine 1-phosphate receptor 1). Forced S1PR1 expression prevented establishment of TRM. Cytokines inducing TRM phenotype (including TGF-β, IL-33 and TNF) provoked KLF2 downregulation in a phosphatidylinositol-3-OH kinase (PI(3)K)–Akt-dependent pathway, suggesting environmental regulation. Hence KLF2 and S1PR1 regulation provides a switch, dictating whether CD8+ T cells commit to the recirculating or tissue resident memory populations.

Immunological memories of the bone marrow

“…It is interesting to note that in the recent hype about “tissue‐resident” memory T lymphocytes, bone marrow‐resident memory T lymphocytes were largely disregarded, quasi the “Cinderella” of memory lymphocytes 154, 155, 156, 157, 158, 159…”

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…CD69 has been shown to negatively regulate expression of sphingosine-1-phosphate receptor, which must be downregulated to establish tissue-residency, 19,20 whereas CD103 binds to the epithelial cell-expressed E-cadherin and is required for maintenance of intestinal T cells. 21 We found that HIC1-deficient CD4 þ and CD8 þ T cells in the LP and intraepithelial compartments expressed significantly reduced levels of CD69 and CD103 (Figures 2c and d).…”

Cutting Edge: CD69 Interference with Sphingosine-1-Phosphate Receptor Function Regulates Peripheral T Cell Retention

“…In line with this, Ccr7 2/2 effector CD8 T cells introduced into uninfected skin fail to exit the injection site and, consequently, show enhanced local conversion into CD69 + CD103 + T RM cells (3). Other migration molecules, such as the sphingosine-1-phosphate (S1P) receptor S1P 1 , have been implicated in the regulation of peripheral T cell accumulation and long-term retention, although its precise function in this process remains to be determined (10,12,13). Effector T cells use S1P 1 to sense S1P gradients among blood, tissues, and lymph, thereby guiding entry into efferent lymphatics during egress from lymphoid tissues (14).…”