Affinage

THEMIS

Protein THEMIS · UniProt Q8N1K5

Length
641 aa
Mass
73.5 kDa
Annotated
2026-04-28
45 papers in source corpus 26 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THEMIS is a T cell lineage-restricted adaptor protein that calibrates TCR signal strength to govern thymocyte positive selection and peripheral T cell homeostasis. It constitutively associates with GRB2 via a PxRPxK motif engaging GRB2's C-terminal SH3 domain, and upon TCR engagement is recruited to the LAT signalosome where it modulates SHP1 phosphatase activity through two complementary mechanisms: its tandem CABIT domains directly inhibit SHP1 by stabilizing oxidation of the catalytic cysteine, while LCK-mediated phosphorylation of THEMIS Tyr34 allosterically activates SHP1 to provide negative feedback on TCR-proximal signaling (PMID:28250424, PMID:38177672, PMID:37159521). Beyond thymocyte selection, THEMIS restrains inhibitory checkpoint receptor signaling (BTLA via SHP1 inactivation; PD-1 expression and signaling via SHP2) and sustains IL-2/IL-15-driven STAT and mTOR signaling in peripheral CD8+ T cells, functions that are corrected by co-deletion of SHP1 (PMID:38713628, PMID:31932808, PMID:35167340). THEMIS also promotes Vav1 activation and ERK signaling downstream of the TCR, contributing to metabolic reprogramming, TH1 effector responses, and regulatory T cell function (PMID:27188442, PMID:26163585, PMID:33177694).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2009 High

    The identification of THEMIS as a T cell-specific protein with tandem CABIT domains that is essential for late thymocyte development established the gene as a critical and previously unknown regulator of thymocyte selection, with knockout mice showing severely reduced single-positive thymocytes and attenuated TCR signaling.

    Evidence Three independent KO and ENU mutagenesis studies with flow cytometry, calcium flux, ERK activation, and transcriptional profiling in mouse thymocytes

    PMID:19597497 PMID:19597498 PMID:19597499

    Open questions at the time
    • Molecular mechanism by which THEMIS influences TCR signal strength was unknown
    • Direct binding partners and signalosome recruitment pathway were not defined
    • Whether THEMIS has functions outside thymocyte development was unexplored
  2. 2010 High

    Mapping THEMIS into the LAT signalosome via GRB2 and demonstrating its requirement for ERK, NFAT/AP-1, and IL-2 signaling established it as a signaling adaptor acting downstream of TCR-proximal kinases rather than a transcription factor or receptor.

    Evidence SILAC phosphoproteomics, Co-IP with LAT/GRB2/PLCγ1, and RNAi knockdown with signaling pathway readouts in Jurkat T cells

    PMID:21189249

    Open questions at the time
    • Precise binding interface between THEMIS and GRB2 was not mapped
    • How THEMIS modulates signal strength at a biochemical level was still unknown
  3. 2013 High

    Defining the constitutive THEMIS-GRB2 interaction through the PxRPxK motif and GRB2 C-SH3, mapping LCK/ZAP-70-dependent tyrosine phosphorylation sites, and demonstrating that this interaction is required for immunological synapse recruitment resolved how THEMIS is physically wired into the TCR signaling cascade.

    Evidence Reciprocal Co-IP, point mutagenesis, confocal imaging of immunological synapse, transgenic mice

    PMID:23460737

    Open questions at the time
    • Enzymatic or regulatory activity of THEMIS itself remained uncharacterized
    • The role of SHP phosphatases in the THEMIS pathway was not yet established
  4. 2013 High

    Demonstrating that THEMIS functions as a signal-strength discriminator — attenuating signaling from low-affinity but not high-affinity TCR ligands via SHP1 — explained how THEMIS sets the threshold distinguishing positive from negative selection.

    Evidence Genetic epistasis in KO mice stimulated with a panel of altered peptide ligands of graded affinity, quantitative signaling measurements

    PMID:24226767

    Open questions at the time
    • Whether THEMIS activates or inhibits SHP1 was debated
    • Biochemical mechanism of THEMIS–SHP1 interaction was not resolved
  5. 2014 High

    The discovery that GRB2 bridges THEMIS to both SHP1 and SHP2 via its two SH3 domains, forming a constitutive ternary complex recruited to LAT, explained how a single adaptor simultaneously delivers phosphatase activity to TCR-proximal substrates such as CD3ζ.

    Evidence Co-IP with GRB2 domain mutants, SHP1/THEMIS knockdown, CD3ζ phosphorylation and signaling assays

    PMID:25535246

    Open questions at the time
    • Whether THEMIS activates SHP1 catalytic activity or merely recruits it was unresolved
    • Structure-function contributions of individual CABIT domains to SHP1 regulation were unknown
  6. 2015 Medium

    Epistasis between THEMIS and Vav1 in regulatory T cell function, with THEMIS stabilizing Vav1 recruitment to LAT and promoting ERK activation, revealed a second effector axis beyond SHP1 through which THEMIS modulates TCR signaling outcomes.

    Evidence Congenic rat lines with Vav1 variants, Co-IP, LAT recruitment assays, Treg suppression assays

    PMID:26163585

    Open questions at the time
    • Whether THEMIS directly contacts Vav1 or acts indirectly via GRB2 was not resolved
    • Relative contribution of SHP1 inhibition versus Vav1 activation to positive selection was unclear
  7. 2016 High

    Quantitative interactomics confirmed SHP-1, GRB2, and Vav1 as principal THEMIS partners and showed that THEMIS promotes Vav1 GEF activity and maintains steady-state GRB2 levels in thymocytes, establishing a broader scaffolding role beyond SHP1 regulation.

    Evidence Quantitative proteomics (interactome) in thymocytes, Vav1 activity assays in Themis-/- and overexpressing cells

    PMID:27188442

    Open questions at the time
    • Mechanism by which THEMIS controls GRB2 protein abundance was not determined
    • Direct versus indirect regulation of Vav1 was not distinguished
  8. 2017 High

    Reconstitution experiments showing that THEMIS CABIT domains directly bind SHP1's phosphatase domain and stabilize oxidation of its catalytic cysteine, combined with genetic rescue of Themis-/- thymocytes by SHP1 deletion, resolved the long-debated mechanism: THEMIS promotes positive selection by inhibiting SHP1 catalytic activity.

    Evidence In vitro phosphatase activity assays, CABIT domain binding, catalytic cysteine oxidation assays, SHP1-deletion genetic epistasis in mice

    PMID:28250424

    Open questions at the time
    • How THEMIS CABIT domains access the buried catalytic cysteine structurally was unknown
    • Whether catalytic cysteine oxidation is the sole mechanism or additional allosteric mechanisms exist was unclear
  9. 2017 Medium

    The discovery that USP9X deubiquitylase is recruited via GRB2 to remove K48-linked ubiquitin chains from THEMIS after TCR stimulation explained how THEMIS protein stability is maintained during signaling.

    Evidence Co-IP, ubiquitin chain analysis, direct binding assays showing USP9X contacts THEMIS N-terminal CABIT domain

    PMID:28877990

    Open questions at the time
    • E3 ubiquitin ligase targeting THEMIS for K48-ubiquitylation was not identified
    • Whether USP9X regulation of THEMIS stability affects positive selection in vivo was not tested
  10. 2018 High

    Sensitive ex vivo phosphatase assays revealed that THEMIS paradoxically enhances SHP1 phosphorylation and catalytic activity in thymocytes, and that SHP2 compensates for SHP1 loss, indicating dual-mode regulation and redundancy among the two phosphatases within the THEMIS complex.

    Evidence Phosphatase activity on ex vivo thymocytes from conditional KO mice, SHP1/SHP2 single and double KO, Co-IP

    PMID:30413615

    Open questions at the time
    • Apparent contradiction between THEMIS inhibiting (cysteine oxidation) versus activating (phosphorylation-dependent) SHP1 was not reconciled
    • Relative importance of SHP1 vs SHP2 in specific selection contexts remained unclear
  11. 2020 High

    Extending THEMIS function beyond the thymus, conditional deletion showed it is required for peripheral CD8+ T cell maintenance, synergistic Akt/mTOR activation from low-affinity pMHC plus cytokine signals, and metabolic reprogramming — all rescued by co-deletion of SHP1 — establishing THEMIS as a tonic signal regulator in mature T cells.

    Evidence Conditional KO in peripheral T cells, Akt phosphorylation, metabolic profiling, double KO rescue with SHP1

    PMID:31932808

    Open questions at the time
    • Whether THEMIS-SHP1 regulation operates identically at TCR versus cytokine receptor signaling complexes was not resolved
    • Role in CD4+ peripheral T cell homeostasis was not fully addressed
  12. 2020 High

    THEMIS was shown to be recruited to the 4-1BB-CAR immunological synapse where it attenuates CAR-CD3ζ signaling via SHP1, providing a mechanistic basis for differential signaling between 4-1BB and CD28 CAR constructs and a rationale for engineering THEMIS-SHP1 recruitment to tune CAR-T cell function.

    Evidence Biochemical synapse analysis of CAR constructs, phosphorylation assays, tumor killing assays

    PMID:32004441

    Open questions at the time
    • Whether THEMIS modulation improves CAR-T therapeutic efficacy in vivo was not tested
    • Structural basis for selective THEMIS recruitment by 4-1BB versus CD28 costimulatory domains was not defined
  13. 2022 High

    Demonstrating that THEMIS is required for IL-2- and IL-15-driven CD8+ T cell proliferation by restraining SHP1 to enable STAT and mTOR signaling extended the THEMIS-SHP1 axis to cytokine receptor signaling, independent of TCR engagement.

    Evidence KO mice, cytokine-driven proliferation assays, STAT/mTOR phosphorylation, metabolomics with stable isotope tracing, SHP1/THEMIS double KO rescue

    PMID:35167340

    Open questions at the time
    • Whether THEMIS is recruited to cytokine receptor complexes directly or acts on a shared SHP1 pool was not determined
    • Applicability to other γc-family cytokines was not tested
  14. 2022 Medium

    Post-thymic conditional deletion revealed TCR-independent THEMIS functions in effector CD4+ T cells: promoting T-bet expression, IFN-γ production, and CNS infiltration in TH1-driven autoimmunity, while inhibiting TCR-mediated TH1 differentiation in naïve cells — demonstrating context-dependent signaling roles.

    Evidence Post-thymic conditional KO, EAE model, cytokine assays, CNS infiltration analysis, in vitro polarization

    PMID:35857631

    Open questions at the time
    • Molecular mechanism of TCR-independent THEMIS function in effector T cells was not identified
    • Whether SHP1 mediates both pro- and anti-inflammatory THEMIS functions was not dissected
  15. 2023 High

    Comprehensive genetic and pharmacologic epistasis confirmed that THEMIS promotes positive selection by inhibiting SHP1 and that negative selection is impaired (not enhanced) in THEMIS absence, resolving earlier ambiguity about THEMIS's role in negative selection and establishing that SHP1 overexpression alone phenocopies THEMIS deficiency.

    Evidence Pharmacologic SHP1 inhibition, Ptpn6 conditional deletion, SHP1 overexpression, multiple KO combinations in thymocytes

    PMID:37159521

    Open questions at the time
    • Why negative selection is also impaired (not just positive selection) without THEMIS was not mechanistically explained
    • Whether the phenocopy by SHP1 overexpression is complete across all thymocyte subsets was not tested
  16. 2023 High

    GRB2 conditional deletion phenocopied THEMIS deficiency in thymocytes — elevated active SHP1, blocked positive selection rescued by SHP1 deletion — confirming that GRB2 is the essential bridge enabling THEMIS-mediated SHP1 inactivation in vivo.

    Evidence Conditional GRB2 KO mice, SHP1 activity assays, SHP1 deletion/overexpression rescue, pharmacologic inhibition

    PMID:37067793

    Open questions at the time
    • Whether GRB2's role in THEMIS function is entirely via SHP1 or also involves Vav1 stabilization was not parsed
  17. 2024 High

    Identification of THEMIS Tyr34 as an LCK-phosphorylated, SHP1-dephosphorylated switch residue that allosterically stabilizes SHP1 in its active conformation revealed a second mechanism — distinct from catalytic cysteine oxidation — by which THEMIS regulates SHP1, and THEMISY34F knock-in mice showed selective impairment of CD4 but not CD8 development.

    Evidence Proximity labeling (PEPSI), saturated mutagenesis, mass spectrometry, allosteric binding assays, knock-in mice

    PMID:38177672

    Open questions at the time
    • How catalytic cysteine oxidation and Tyr34-mediated allosteric activation are coordinated in time and space was not resolved
    • Why CD4 but not CD8 selection depends on the Tyr34 switch is unexplained
  18. 2024 High

    THEMIS was shown to be recruited to the BTLA cytoplasmic domain where it inactivates SHP1 by catalytic cysteine oxidation, blocking BTLA-mediated inhibition of TCR, IL-2, and IL-15 signaling; THEMIS had no effect on PD-1 signaling (which depends on SHP2), establishing receptor specificity in checkpoint regulation.

    Evidence Co-IP (THEMIS-BTLA), SHP-1 oxidation assays, conditional KO mice, signaling pathway analysis

    PMID:38713628

    Open questions at the time
    • Whether THEMIS is recruited to other ITIM/ITSM-containing inhibitory receptors beyond BTLA was not tested
    • How THEMIS selectivity for SHP1 over SHP2 at BTLA is achieved structurally is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how the two distinct THEMIS mechanisms for SHP1 regulation (catalytic cysteine oxidation by CABIT domains versus Tyr34-mediated allosteric activation) are temporally and spatially coordinated during selection; the structural basis for THEMIS CABIT domain access to SHP1's catalytic site; and whether THEMIS functions at additional inhibitory receptors or cytokine receptor complexes beyond those currently identified.
  • No integrated structural model of the full THEMIS-GRB2-SHP1 ternary complex exists
  • Temporal coordination of oxidation-based inhibition versus Tyr34-based activation of SHP1 is not resolved
  • Role of THEMIS at inhibitory receptors beyond BTLA and PD-1 has not been surveyed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 4
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
BTLAGRB2LATLCKPTPN11PTPN6USP9XVAV1
Complex memberships
LAT signalosomeTHEMIS-GRB2-SHP1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 THEMIS is a T cell-specific protein required for late thymocyte development; Themis-/- mice show impaired thymocyte selection and reduced CD4+ and CD8+ single-positive thymocytes, with developmental defects consistent with attenuated TCR signaling that are reversible by TCR stimulation. Genetic knockout mouse model with flow cytometry and TCR stimulation rescue experiments Nature immunology High 19597498
2009 THEMIS is phosphorylated rapidly after TCR stimulation and is required for optimal TCR-driven calcium mobilization and ERK activation; it belongs to a conserved protein family containing CABIT domains. Genetic knockout mice, phosphorylation assays, calcium flux measurements, ERK activation assays Nature immunology High 19597499
2009 THEMIS contains tandem CABIT domains and is a founding member of a new metazoan gene family; Themis-deficient thymocytes show no substantial early TCR signaling impairment but show altered expression of genes involved in cell cycle and survival during positive selection. ENU mutagenesis screen, genetic knockout, gene expression analysis Nature immunology High 19597497
2010 THEMIS tyrosine phosphorylation depends on the scaffold proteins LAT and SLP-76; THEMIS associates with LAT (via GRB2) and with PLCγ1; THEMIS knockdown inhibits TCR-induced IL-2 gene expression, ERK, and NFAT/AP-1 signaling but not JNK, p38, or NF-κB activation. SILAC-based quantitative phosphoproteomics, Co-IP, RNAi knockdown, signaling assays The Journal of biological chemistry High 21189249
2012 Themis2 (expressed in B cells and macrophages) can functionally replace Themis1 in thymocyte development; both proteins are tyrosine phosphorylated and recruited within GRB2 signaling complexes to LAT following TCR engagement, indicating conserved molecular function. Transgenic rescue of Themis1-/- mice with Themis1 or Themis2 transgenes, Co-IP, flow cytometry Journal of immunology High 22732588
2013 THEMIS constitutively associates with GRB2 through a conserved PxRPxK motif in its proline-rich region 1 binding to the C-terminal SH3 domain of GRB2; this interaction is required for THEMIS recruitment to the immunological synapse via LAT and for THEMIS phosphorylation by LCK and ZAP-70; two major tyrosine phosphorylation sites were mapped to a YY-motif near proline-rich region 1. Co-IP, mutational analysis, confocal microscopy of immunological synapse, transgenic mice Journal of immunology High 23460737
2013 THEMIS acts as an analog-to-digital converter, specifically attenuating TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement, thereby setting the threshold for positive versus negative selection. Genetic knockout mice, epistasis analysis, TCR stimulation with varied-affinity ligands, signaling assays Nature High 24226767
2014 THEMIS constitutively associates with both SHP1 and SHP2 phosphatases; this complex requires the adapter GRB2, which bridges SHP to THEMIS via its N-SH3 and C-SH3 domains respectively, allowing GRB2-SH2 to recruit the complex onto LAT; THEMIS-mediated SHP recruitment dampens TCR-proximal CD3-ζ phosphorylation, ERK activation, and CD69 expression to promote T cell survival. Co-IP, GRB2 domain-mapping, THEMIS knockdown, SHP1 knockdown, signaling assays The EMBO journal High 25535246
2014 THEMIS functional coupling to LCK tyrosine kinase is required for experimental cerebral malaria pathogenesis; an I23N mutation abolishes THEMIS protein stability, and doubly heterozygous Themis(I23N/+):Lck(-/+) mice fail to complement, demonstrating LCK-THEMIS functional coupling in vivo. ENU mutagenesis, in vitro stability assays, in vivo genetic complementation (double heterozygotes) Infection and immunity Medium 25452553
2014 All conserved THEMIS domains (PRS, NLS, CABIT1, CABIT2) are required for positive selection; deletion of Core1 but not Core2 caused dominant-negative inhibition of T cell development; NLS and Core1 are required for nuclear localization of THEMIS. Transgenic rescue experiments with domain-deletion mutants in Themis-/- mice, flow cytometry, microscopy PloS one Medium 24586531
2016 THEMIS1 promotes Vav1 activity (guanine nucleotide exchange factor) both in vitro and in vivo and is required to maintain steady-state abundance of GRB2 in thymocytes; the interactome of THEMIS1 in thymocytes includes SHP-1, GRB2, and Vav1 as principal partners. Quantitative proteomics (interactome), TCR signaling reporter mice, Vav1 activity assays in Themis1-/- and Themis1-overexpressing thymocytes Science signaling High 27188442
2017 THEMIS directly inhibits the catalytic activity of SHP-1 via its CABIT modules, which bind to the phosphatase domain of SHP-1 and promote or stabilize oxidation of SHP-1's catalytic cysteine; deletion of SHP-1 alleviates the developmental block in Themis-/- thymocytes. In vitro phosphatase activity assays, CABIT domain binding studies, SHP-1 catalytic cysteine oxidation assays, genetic epistasis (SHP-1 deletion rescue) Nature immunology High 28250424
2017 GRB2-mediated recruitment of the deubiquitylase USP9X to LAT stabilizes THEMIS protein by removing K48-linked ubiquitin chains from THEMIS following TCR engagement; USP9X binds directly to the N-terminal CABIT domain of THEMIS. Biochemical analysis (Co-IP, ubiquitin chain analysis), THEMIS mRNA vs protein level comparison, direct binding assays Journal of immunology Medium 28877990
2018 THEMIS enhances SHP1 phosphatase activity by increasing SHP1 phosphorylation in thymocytes (but not peripheral T cells); this enhancement is specific to thymocytes and modulated by TCR ligand affinity; in the absence of SHP1, THEMIS associates with SHP2 to maintain near-normal thymic development; double deletion of THEMIS and SHP1 phenocopies THEMIS KO. Sensitive phosphatase assay on ex vivo thymocytes, conditional KO mice, SHP1/SHP2 single and double KO, Co-IP PNAS High 30413615
2020 THEMIS is required for maintenance of peripheral CD8+ T cells and for proliferative CD8+ T cell responses to low-affinity pMHC aided by cytokines; THEMIS promotes synergistic phosphorylation of Akt, metabolic changes, and c-Myc induction from low-affinity pMHC plus cytokine signals; this function is mediated through SHP1, as peripheral Themis and Shp1 double deletion rescues peripheral CD8+ T cell maintenance. Conditional deletion, TCR stimulation assays, Akt phosphorylation, metabolic profiling, genetic epistasis (double KO rescue) Nature immunology High 31932808
2020 In 4-1BB-encoding CAR-T cells, the THEMIS-SHP1 phosphatase complex is recruited to the CAR synapse and attenuates CAR-CD3ζ phosphorylation, contrasting with CD28-encoding CARs where LCK is recruited instead; engineering the synapse to recruit SHP1 tunes down cytokine release of CD28 CAR-T cells. Biochemical synapse analysis, CAR engineering, phosphorylation assays, tumor killing assays Cancer cell High 32004441
2020 THEMIS-deficient CD4+ T cells show reduced NFAT nuclear translocation upon TCR stimulation, leading to failure to upregulate insulin receptor, GLUT1, CD98, and mTOR pathway components, and defective metabolic reprogramming (more OXPHOS than aerobic glycolysis). Conditional deletion, NFAT translocation assays, metabolic profiling, ChIP-seq/RNA-seq data analysis Cellular & molecular immunology Medium 33177694
2022 THEMIS is required for IL-2- and IL-15-driven CD8+ T cell proliferation; mechanistically, THEMIS promotes STAT and mTOR signaling downstream of cytokine receptors, and the metabolic and biochemical defects of THEMIS deficiency are corrected by co-deletion of SHP1, indicating THEMIS restrains SHP1 to enable cytokine receptor-proximal signaling. KO mice, in vitro proliferation assays, STAT and mTOR phosphorylation, metabolomics, stable isotope tracing, SHP1/THEMIS double KO Science signaling High 35167340
2022 THEMIS promotes optimal type 1 (TH1) immune responses in effector CD4+ T cells via TCR-independent functions; THEMIS is required for T-bet expression and IFN-γ production and enhances the ability of encephalitogenic CD4+ T cells to migrate into the CNS; in contrast, THEMIS inhibits TCR-mediated signals leading to TH1 responses in naïve CD4+ T cells. Post-thymic conditional deletion, immunization models, cytokine assays, CNS infiltration analysis, in vitro T cell polarization Science signaling Medium 35857631
2023 THEMIS promotes positive selection by inhibiting SHP1 activity; pharmacologic SHP1 inhibition or Ptpn6 deletion ameliorates the positive selection defect in Themis-/- thymocytes, while SHP1 overexpression exacerbates it and phenocopies THEMIS deficiency; negative selection is impaired (not enhanced) in the absence of THEMIS. Pharmacologic inhibition, conditional and full KO mice, SHP1 overexpression, genetic epistasis (Ptpn6, Ptpn11, double deletion) Science signaling High 37159521
2023 THEMIS mediates PD-1 expression and PD-1 signaling in effector CD8+ T cells; THEMIS deficiency impairs memory precursor (MPEC) differentiation while promoting short-lived effector cell (SLEC) differentiation and enhances effector cytokine production. Conditional KO mice, LCMV infection model, flow cytometry, cytokine production assays Cellular & molecular immunology Medium 36977779
2023 GRB2 promotes thymocyte positive selection principally by facilitating THEMIS-mediated inactivation of SHP1; GRB2-deficient thymocytes have increased catalytically active SHP1, and their developmental block is alleviated by SHP1 deletion/inhibition and exacerbated by SHP1 overexpression, paralleling the THEMIS KO phenotype. Conditional GRB2 KO mice, SHP1 activity assays, genetic rescue (SHP1 deletion), SHP1 overexpression, pharmacologic inhibition The Journal of experimental medicine High 37067793
2024 THEMIS is an uncharacterized substrate of SHP1; phosphorylation of THEMIS at the conserved Tyr34 residue is promoted by LCK and reversed by SHP1; phospho-Tyr34 acts as an allosteric regulator that binds and stabilizes SHP1 in its active conformation; THEMISY34F knock-in mice show decreased CD4 thymocytes and mature CD4 T cells but normal CD8 development. Proximity labeling (PEPSI), saturated mutagenesis, mass spectrometry, knock-in mice, allosteric binding assays Nature structural & molecular biology High 38177672
2024 THEMIS is recruited to the cytoplasmic domain of BTLA and blocks BTLA signaling by promoting/stabilizing oxidation of the catalytic cysteine of SHP-1; THEMIS has no effect on PD-1 signaling (which depends mainly on SHP-2); in the absence of THEMIS, BTLA signaling is exacerbated, attenuating TCR, IL-2, and IL-15 receptor signals. Co-IP, SHP-1 oxidation assays, conditional KO mice, signaling pathway analysis PNAS High 38713628
2015 Epistasis between THEMIS1 and Vav1 controls Treg suppressive function; THEMIS1 binds preferentially to the BN Vav1-W63 variant and stabilizes its recruitment to LAT, promoting ERK kinase activation; introduction of Lewis Vav1-R63 variant restores Treg function in Themis1-deficient BN rats. Congenic rat lines, Co-IP, LAT recruitment assays, ERK activation assays, Treg suppression assays Journal of immunology Medium 26163585
2024 THEMIS promotes Vav1 phosphorylation in CD4 T cells and enhances encephalitogenic Tconv responses; combined Vav1(R63W) hypomorphic mutation and T cell-conditional THEMIS deletion synergistically attenuates EAE severity by reducing phospho-Vav1, pro-inflammatory cytokines, and CNS T cell infiltration. Conditional KO mice, hypomorphic Vav1 knock-in, EAE model, phospho-Vav1 assays, cytokine measurements Cellular and molecular life sciences Medium 38565808
2025 Cryo-EM structure of the THEMIS-GRB2 complex reveals that the tandem CABIT domains of THEMIS engulf the C-terminal SH3 domain of GRB2 (Grb2 SH3C) to enable latching onto the proline-rich sequence of THEMIS; THEMIS variants that abrogate GRB2 interaction also fail to activate SHP-1 after TCR stimulation. Cryo-EM structure determination, mutagenesis, SHP-1 activation assays bioRxivpreprint High
2025 THEMIS binds to PD-1 and promotes PD-1 phosphorylation and its recruitment of SHP2, mediating PD-1 signaling as a negative regulator to inhibit T cell effector functions; THEMIS initially promotes TCR signaling to induce PD-1 expression and subsequently mediates PD-1 signaling. Conditional KO mice, chronic LCMV infection model, Co-IP (THEMIS-PD-1), phosphorylation assays, single-cell analysis bioRxivpreprint Medium
2024 Crystal structure of the THEMIS CABIT2 domain at 2.9 Å reveals a novel protein fold comprising mainly β-sheets with two distinct subdomains; inclusion of the proline-rich segment enables GRB2 binding to CABIT2; isolated CABIT2 domain alone cannot bind or modulate SHP1 phosphatase activity. X-ray crystallography (heavy atom phasing), GRB2 binding assays, SHP1 activity assay bioRxivpreprint Medium

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Themis, a T cell-specific protein important for late thymocyte development. Nature immunology 124 19597498
2020 THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells. Cancer cell 122 32004441
2009 Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nature immunology 121 19597499
2013 Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 102 24226767
2009 Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nature immunology 102 19597497
2014 A THEMIS:SHP1 complex promotes T-cell survival. The EMBO journal 79 25535246
2010 T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component. The Journal of biological chemistry 72 21189249
2017 THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1. Nature immunology 70 28250424
2013 GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development. Journal of immunology (Baltimore, Md. : 1950) 68 23460737
2020 T cell receptor and cytokine signal integration in CD8+ T cells is mediated by the protein Themis. Nature immunology 41 31932808
2016 Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability. Science signaling 34 27188442
2012 Interchangeability of Themis1 and Themis2 in thymocyte development reveals two related proteins with conserved molecular function. Journal of immunology (Baltimore, Md. : 1950) 32 22732588
2012 A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease. PLoS genetics 30 22275874
2013 THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge. European journal of human genetics : EJHG 28 23820479
2015 THEMIS: a critical TCR signal regulator for ligand discrimination. Current opinion in immunology 27 25700024
2014 THEMIS is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis. Infection and immunity 24 25452553
2017 THEMIS: Two Models, Different Thresholds. Trends in immunology 21 28697966
2018 Themis-associated phosphatase activity controls signaling in T cell development. Proceedings of the National Academy of Sciences of the United States of America 20 30413615
2020 Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation. Cellular & molecular immunology 19 33177694
2022 Themis is indispensable for IL-2 and IL-15 signaling in T cells. Science signaling 18 35167340
2017 Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function. Molecular & cellular proteomics : MCP 18 28373295
2010 Contiguous gene deletion of Ptprk and Themis causes T-helper immunodeficiency (thid) in the LEC rat. Biomedical research (Tokyo, Japan) 15 20203423
2015 An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development. Journal of immunology (Baltimore, Md. : 1950) 14 26163585
2016 Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis. PloS one 13 27438997
2022 THEMIS enhances the magnitude of normal and neuroinflammatory type 1 immune responses by promoting TCR-independent signals. Science signaling 11 35857631
2017 Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection. Journal of immunology (Baltimore, Md. : 1950) 11 28877990
2014 Differential function of Themis CABIT domains during T cell development. PloS one 11 24586531
2023 Themis suppresses the effector function of CD8+ T cells in acute viral infection. Cellular & molecular immunology 10 36977779
2023 THEMIS increases TCR signaling in CD4+CD8+ thymocytes by inhibiting the activity of the tyrosine phosphatase SHP1. Science signaling 9 37159521
2022 Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses. Biomedical journal 9 35346866
2024 THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA. Proceedings of the National Academy of Sciences of the United States of America 8 38713628
2023 Themis controls T cell activation, effector functions, and metabolism of peripheral CD8+ T cells. Life science alliance 8 37739454
2024 THEMIS is a substrate and allosteric activator of SHP1, playing dual roles during T cell development. Nature structural & molecular biology 7 38177672
2023 GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1. The Journal of experimental medicine 7 37067793
2021 Expansion of an Unusual Virtual Memory CD8+ Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice. Frontiers in immunology 6 33897691
2014 In vivo functional mapping of the conserved protein domains within murine Themis1. Immunology and cell biology 5 24935457
2024 Positive regulation of Vav1 by Themis controls CD4 T cell pathogenicity in a mouse model of central nervous system inflammation. Cellular and molecular life sciences : CMLS 4 38565808
2013 cDNA cloning, localization, and candidate binding partners of acid-extractable vitelline-coat protein Ci-v-Themis-like in the ascidian Ciona intestinalis. Molecular reproduction and development 3 23857746
2024 A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice. The Journal of allergy and clinical immunology 2 38670234
2024 Themis: advancing precision oncology through comprehensive molecular subtyping and optimization. Briefings in bioinformatics 2 38833322
2026 Role of Themis in peripheral CD8 T cells in hapten-induced allergic skin inflammation. International immunology 0 40887931
2026 THEMIS: new insights into its evolution, structure, and function. Trends in immunology 0 41925413
2025 Themis differentially regulates T follicular helper cell differentiation during early and late stages of chronic viral infection. Frontiers in immunology 0 40777021
2025 The role of Themis in development of type 2 diabetes. Research square 0 41282140
2023 A mutation in Themis contributes to peanut-induced oral anaphylaxis in CC027 mice. bioRxiv : the preprint server for biology 0 37745496