Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling

Fu, Guo; Vallée, Sébastien; Rybakin, Vasily; McGuire, Marielena V.; Ampudia, Jeanette; Brockmeyer, Claudia; Salek, Mogjiborahman; Fallen, Paul R; Hoerter, John A. H.; Munshi, Anil; Huang, Yina H.; Hu, Jianfang; Fox, Howard S.; Sauer, Karsten; Acuto, Oreste; Gascoigne, Nicholas R. J.

doi:10.1038/ni.1766

Cited by 132 publications

(202 citation statements)

References 44 publications

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“…Despite the absence of strong biochemical evidence, it was presumed that Themis1 likely functions as a positive regulator of TCR signaling because several defects in Themis1 −/− mice, such as a marked impairment of both positive and negative selection, were consistent with a deficiency in TCR signaling (2)(3)(4)(5)(6). It was subsequently shown that Themis1 interacts with Vav1 and that Vav1 phosphorylation is reduced in Themis1 −/− thymocytes, results that also implied a positive role for Themis1 in TCR signaling (9).…”

Section: Discussionmentioning

confidence: 99%

“…We and others identified the previously uncharacterized protein Themis1 as being required for the positive selection and maturation of T cells in the thymus (2)(3)(4)(5)(6). Themis1 lacks any discernable catalytic domain, but it contains two previously uncharacterized cysteine-based globular domains (named "CABIT") of unknown structure and function (3).…”

Section: Introductionmentioning

confidence: 99%

“…The cell surface abundance of the signaling sensor CD5 is reduced in CD4 + CD8 lo Themis1 −/− thymocytes (5), whereas that of CD69 is decreased in the absence of Themis1 in preselected OT-I TCR transgenic CD4 + CD8 + thymocytes [referred to as double-positive (DP) thymocytes] after stimulation through ovalbumin peptide-conjugated tetramers (2). In addition, negative selection and CD4 + T cell lineage commitment, which are dependent on intense or sustained TCR signals, respectively, are both impaired in Themis1 −/− mice (2,5).…”

Section: Introductionmentioning

confidence: 99%

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Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain-containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1 −/− mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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“…We would like to note that, during the review process of this article, several other groups' reports describing the same gene under the name "Themis" were published (33)(34)(35)40).…”

Section: Discussionmentioning

confidence: 99%

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Patrick

Oda²,

Hayakawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

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T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCRinduced events such as ␤-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocytespecific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection. (2). The fate of individual DP thymocytes is determined by the strength of affinity and longevity of interaction between their TCR and peptide:MHC ligand (3). Although it is known that strong TCR/ligand interaction leads to negative selection and weak association results in positive selection (4), how this quantitative difference of TCR interaction can be converted to the qualitative difference is not known. Therefore, it is important to investigate the difference in molecular mechanisms of positive and negative selection.

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“…THEMIS expression is limited to lymphoid tissues, and studies in mice have shown that it encodes an important molecule for T-cell development, being expressed at higher levels in pre-TcR thymocytes. 5 Although its expression is reduced in differentiated T lymphocytes, 6 it is thought to have a role in TcR activation signaling. 7 In turn, PTPRK performs functions related to the maintenance of cell junctions [8][9][10] and in the modulation of epidermal growth factor receptor (EGFR) activity, resulting in an inhibition of cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge

et al. 2013

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Celiac disease (CD) is an immune mediated, polygenic disorder, where HLA-DQ2/DQ8 alleles contribute around 35% to genetic risk, but several other genes are also involved. Genome-wide association studies (GWASs) and the more recent immunochip genotyping projects have fine-mapped 39 regions of genetic susceptibility to the disease, most of which harbor candidate genes that could participate in this disease process. We focused our attention to the GWAS peak on chr6: 127.99-128.38 Mb, a region including two genes, thymocyte-expressed molecule involved in selection (THEMIS) and protein tyrosine phosphatase, receptor type, kappa (PTPRK), both of which have immune-related functions. The aim of this work was to evaluate the expression levels of these two genes in duodenal mucosa of active and treated CD patients and in controls, and to determine whether SNPs (rs802734, rs55743914, rs72975916, rs10484718 and rs9491896) associated with CD have any influence on gene expression. THEMIS showed higher expression in active CD compared with treated patients and controls, whereas PTPRK showed lower expression. Our study confirmed the association of this region with CD in our population, but only the genotype of rs802734 showed some influence in the expression of THEMIS. On the other hand, we found a significant positive correlation between THEMIS and PTPRK mRNA levels in CD patients but not in controls. Our results suggest a possible role for both candidate genes in CD pathogenesis and the existence of complex, regulatory relationships that reside in the vast non-coding, functional intergenic regions of the genome. Further investigation is needed to clarify the impact of the disease-associated SNPs on gene function.

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Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling

Cited by 132 publications

References 44 publications

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge

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