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      The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin.

      Nature immunology
      Animals, Antigens, CD, genetics, immunology, metabolism, Antigens, Differentiation, T-Lymphocyte, CD8-Positive T-Lymphocytes, virology, Cell Differentiation, Flow Cytometry, Herpes Simplex, Herpesvirus 1, Human, physiology, Host-Pathogen Interactions, Immunologic Memory, Integrin alpha Chains, Interleukin-15, Lectins, C-Type, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Protein-Serine-Threonine Kinases, Receptors, Immunologic, Receptors, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Skin, Transcriptome

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          Abstract

          Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Lineage relationship and protective immunity of memory CD8 T cell subsets.

            Memory CD8 T cells can be divided into two subsets, central (T(CM)) and effector (T(EM)), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. Our results show that T(CM) have a greater capacity than T(EM) to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential. We also demonstrate that, following antigen clearance, T(EM) convert to T(CM) and that the duration of this differentiation is programmed within the first week after immunization. We propose that T(CM) and T(EM) do not necessarily represent distinct subsets, but are part of a continuum in a linear naive --> effector --> T(EM) --> T(CM) differentiation pathway.
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              T-cell function and migration. Two sides of the same coin.

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