Journal Article

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

Lee, June-Yong, Masopust, David, Jameson, Stephen C, Skon, Cara N, Anderson, Kristin G, Hogquist, Kristin A

2013

Overview

Jameson and colleagues show that the establishment of resident memory CD8 + T cells in nonlymphoid tissues requires transcriptional downregulation of the trafficking molecule S1P 1 , mediated by induced loss of the transcription factor KLF2. 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 (T RM cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of T RM cells is unknown. We found that CD8 + T RM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P 1 , a receptor for sphingosine 1-phosphate). Forced expression of S1P 1 prevented the establishment of T RM cells. Cytokines that induced a T RM 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 S1P 1 provides a switch that dictates whether CD8 + T cells commit to recirculating or tissue-resident memory populations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/31 / 14 / 38/77 / 631/250/1619/554/1834 / 631/250/2152/1566/1571 / 631/250/347 / Animals / Antigens, CD - genetics / Antigens, CD - immunology / Antigens, CD - metabolism / Antigens, Differentiation, T-Lymphocyte - genetics / Antigens, Differentiation, T-Lymphocyte - immunology / Antigens, Differentiation, T-Lymphocyte - metabolism / Biomedicine / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cells, Cultured / Down-Regulation - drug effects / Down-Regulation - immunology / Environmental regulations / Flow Cytometry / Immunologic Memory - immunology / Immunology / Infectious Diseases / Interleukin-33 / Interleukins - pharmacology / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - immunology / Kruppel-Like Transcription Factors - metabolism / Lectins, C-Type - genetics / Lectins, C-Type - immunology / Lectins, C-Type - metabolism / Lymphocytes / Mice, Inbred C57BL / Mice, Inbred Strains / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - immunology / Phosphatidylinositol 3-Kinases - metabolism / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - immunology / Proto-Oncogene Proteins c-akt - metabolism / Receptors, Lysosphingolipid - genetics / Receptors, Lysosphingolipid - immunology / Receptors, Lysosphingolipid - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction - drug effects / Signal Transduction - genetics / Signal Transduction - immunology / Transcription, Genetic - drug effects / Transcription, Genetic - immunology / Transforming Growth Factor beta - pharmacology / Tumor Necrosis Factor-alpha - pharmacology