Identification of Pre- and Postselection TCRαβ+ Intraepithelial Lymphocyte Precursors in the Thymus

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144

115

Mouse small intestine intraepithelial lymphocytes (IEL) that express αβTCR and CD8αα homodimers are an enigmatic T cell subset, as their specificity and in vivo function remain to be defined. To gain insight into the nature of these cells, we performed global gene expression profiling using microarray analysis combined with real-time quantitative PCR and flow cytometry. Using these methods, TCRαβ+CD8αα IEL were compared with their TCRαβ+CD8β+ and TCRγδ+ counterparts. Interestingly, TCRαβ+CD8αα IEL were found to preferentially express genes that would be expected to down-modulate their reactivity. They have a unique expression pattern of members of the Ly49 family of NK receptors and tend to express inhibitory receptors, along with some activating receptors. The signaling machinery of both TCRαβ+CD8αα and TCRγδ+ IEL is constructed differently than other IEL and peripheral T cells, as evidenced by their low-level expression of the linker for activation of T cells and high expression of the non-T cell activation linker, which suppresses T cell activation. The TCRαβ+CD8αα IEL subset also has increased expression of genes that could be involved in immune regulation, including TGF-β3 and lymphocyte activation gene-3. Collectively, these data underscore the fact that, while TCRαβ+CD8αα IEL resemble TCRγδ+ IEL, they are a unique population of cells with regulated Ag reactivity that could have regulatory function.

Section: Discussionsupporting

confidence: 92%

Section: Riphery (3) Perhaps As a Results Of Contact With Dendritic Cmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mouse TCRαβ+CD8αα Intraepithelial Lymphocytes Express Genes That Down-Regulate Their Antigen Reactivity and Suppress Immune Responses

Denning

Granger

Mucida

et al. 2007

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144

115

“…Indeed, a recent report indicates that triple-positive thymocytes (CD4 ϩ CD8␣␤ ϩ CD8␣ ϩ ) represent the preselection stage; however, double-negative CD5 ϩ TCR␤ ϩ thymocytes are postselection precursors of the CD8␣␣ iIELs. These precursors require further maturation into CD8␣␣ iIELs after export from the thymus in an IL-15-rich environment, e.g., the gut (36).…”

Section: Discussionmentioning

confidence: 99%

Anti-TCR Antibody Treatment Activates a Novel Population of Nonintestinal CD8αα+TCRαβ+ Regulatory T Cells and Prevents Experimental Autoimmune Encephalomyelitis

Tang

Maricic

Kumar

2007

CD8αα+CD4−TCRαβ+ T cells are a special lineage of T cells found predominantly within the intestine as intraepithelial lymphocytes and have been shown to be involved in the maintenance of immune homeostasis. Although these cells are independent of classical MHC class I (class Ia) molecules, their origin and function in peripheral lymphoid tissues are unknown. We have recently identified a novel subset of nonintestinal CD8αα+CD4−TCRαβ+ regulatory T cells (CD8αα Tregs) that recognize a TCR peptide from the conserved CDR2 region of the TCR Vβ8.2-chain in the context of a class Ib molecule, Qa-1a, and control- activated Vβ8.2+ T cells mediating experimental autoimmune encephalomyelitis. Using flow cytometry, spectratyping, and real-time PCR analysis of T cell clones and short-term lines, we have determined the TCR repertoire of the CD8αα regulatory T cells (Tregs) and found that they predominantly use the TCR Vβ6 gene segment. In vivo injection of anti-TCR Vβ6 mAb results in activation of the CD8αα Tregs, inhibition of the Th1-like pathogenic response to the immunizing Ag, and protection from experimental autoimmune encephalomyelitis. These data suggest that activation of the CD8αα Tregs present in peripheral lymphoid organs other than the gut can be exploited for the control of T cell-mediated autoimmune diseases.

“…Although iNKT and siIEL recognize Ags differently, they resemble each other in many ways. They exert their effector functions more rapidly than their adaptive counterparts and exhibit tissue-restricted homing and distribution, an activated phenotype, use of a restricted TCR repertoire (9,10), and agonist-mediated thymic selection, development, and maturation (11,12) iNKTs are CD1d-restricted T cells that reside predominantly in the liver and spleen, but are also found in lung and peripheral lymph nodes. iNKTs express a canonical Va14-Ja18 TCRa-chain that can pair with either Vb8, Vb7, or Vb2 (10), and are selected on double-positive (DP) thymocytes via homotypic interactions of SLAM family receptors (13).…”

mentioning

confidence: 99%

Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells

Chennupati

Koch

Coutaz

et al. 2016

Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis.