T Cell Receptor-Interacting Molecule Acts as a Chaperone to Modulate Surface Expression of the CTLA-4 Coreceptor

Valk, Elke; Leung, Rufina; Kang, Hyo-Jin; Kaneko, Kazuyo; Rudd, Christopher E.; Schneider, Helga

doi:10.1016/j.immuni.2006.08.024

Cited by 69 publications

(71 citation statements)

References 52 publications

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“…CTLA-4 expression can be modified by increased transport to the cell surface. For instance, the T-cell receptor interacting molecule associates with CTLA-4 and promotes its delivery to the cell surface [47]. This results in increased CTLA-4 expression despite an increased rate of CTLA-4 internalisation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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“…Murine CD4 ϩ T cells were activated with plate-bound anti-CD3/CD28 for 48 hours, before transfection with 2 g CTLA-4-GFP or vector (pEGFP) per 1 ϫ 10 6 cells using the Amaxa Nucleofector Kit (Lonza), as described 34 ( Figure 1). Cells were then maintained in culture without anti-CD3/CD28 for 24 hours (ie, rested) followed by analysis of motility.…”

Section: Cell Motility Assaysmentioning

confidence: 99%

Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal

Schneider

Rudd

2012

Blood

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CTLA-4 inhibits T-cell activation and protects against the development of autoimmunity. We and others previously showed that the coreceptor can induce T-cell motility and shorten dwell times with dendritic cells (DCs). However, it has been unclear whether this property of CTLA-4 affects both conventional T cells (Tconvs) and regulatory T cells (Tregs). Here, we report that CTLA-4 had significantly more potent effects on the motility and contact times of Tconvs than Tregs. This was shown firstly by anti-CTLA-4 reversal of the anti-CD3 stop-signal on FoxP3-negative cells at concentrations that had no effect on FoxP3-positive Tregs. Secondly, the presence of CTLA-4 reduced the contact times of DO11.10 x CD4 ؉ CD25 ؊ Tconvs, but not DO11. IntroductionT-cell responses require an antigen-specific signal generated by the TCR/CD3 and CD4-CD8-p56 lck complexes 1,2 as well as by coreceptors, such as CD28, inducible T-cell costimulator (ICOS), CTLA-4, and programmed death-1 (PD-1). 3,4 CTLA-4 is inhibitory as demonstrated by the phenotype of Ctla4 Ϫ/Ϫ mice that develop a lymphoproliferative disorder characterized by massive tissue infiltration and early lethality. 5,6 CTLA-4 raises the threshold that is needed for T-cell activation by cell intrinsic and extrinsic pathways. 7 Cell intrinsic mechanisms include inhibition of ZAP-70 microcluster formation, 8 an altered immunologic synapse (IS), 9 modulation of TCR signaling by phosphatases SHP-2 and PP2A, 10,11 and interference with the expression or composition of lipid rafts on the surface of T cells. [12][13][14] Cell extrinsic functions include the ecto-domain competition for CD28 binding to CD80/CD86, 15 occupancy or removal of CD80/86 16 or the release of indoleamine 2,3-dioxygenase (IDO) 17 and transforming growth factor ␤ (TGF-␤). 18 CTLA-4 expression is also needed for optimal suppression by regulatory T cells (Tregs). 19 The external domain of CTLA-4 has been reported to mediate anergy induction, whereas its effect in reducing TCR signaling required the internal domain. 20 In this context, we have shown that CTLA-4 induces T-cell motility (ie, motility activator) and limits contact times with DCs as well as affecting the migration of T cells in lymph nodes. 8,21,22 Reduced contact times by CTLA-4 would be expected to limit TCR ligation events and raise the threshold for T-cell activation. [21][22][23][24] The motility inducing effects of CTLA-4 have been confirmed by several laboratories in various in vivo models, [25][26][27] and involves CTLA-4 activation of the GTP binding protein Rap1 and LFA-1 adhesion. 24,28 Immune responses are regulated by a balance of inflammatory responses by conventional or responder T cells (Tconvs) and suppression by Tregs that maintain tolerance to self-antigen. 29,30 Treg suppression of the in vitro proliferation of Tconvs is cellcontact-dependent. 31 Further, Tregs constitutively express CTLA-4 which can be released to the cell surface and is needed for optimal suppressor function. 19,32,33 In this context, it has been unclear whethe...

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“…Jurkat T-cells (ATCC, American Type Culture Collection, VA, USA ) were cultured in RPMI 1640 supplemented with 5 % fetal calf serum (FCS), 2 mM L-glutamine and 100 U/ml penicillin/streptomycin [7]. Anti-CD3 (OKT3) was obtained from the ATCC and anti-human CTLA-4 mAb was provided by Dr. Broeker (Greifswald, Germany).…”

Section: Experimental Cells and Reagentsmentioning

confidence: 99%

“…Recently, the small transmembrane adaptor protein T cell receptorinteracting molecule (TRIM) was found to bind to CTLA-4 leading to enhanced CTLA-4 surface expression [7].…”

Section: Identificationmentioning

confidence: 99%

Cytotoxic T-lymphocyte Antigen-4 Binding to SHP2 Interacting Transmembrane Adapter Protein by Phosphorylation in T-Cell

Lee¹,

Kang²

2015

Trop. J. Pharm Res

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T Cell Receptor-Interacting Molecule Acts as a Chaperone to Modulate Surface Expression of the CTLA-4 Coreceptor

Cited by 69 publications

References 52 publications

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal

Cytotoxic T-lymphocyte Antigen-4 Binding to SHP2 Interacting Transmembrane Adapter Protein by Phosphorylation in T-Cell

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