Molecular Basis of T Cell Inactivation by CTLA-4

Lee, Kyung Mi; Chuang, Ellen; Griffin, Matthew D.; Khattri, Roli; Hong, David K.; Zhang, Weiguo; Straus, David B.; Samelson, Lawrence E.; Thompson, Craig B.; Bluestone, Jeffrey A.

doi:10.1126/science.282.5397.2263

Cited by 618 publications

(449 citation statements)

References 28 publications

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“…Activated or memory-type T cells including T cell clones may be susceptible to an alternative inhibitory mechanism through TR-CTLA-4 that does not require the cytoplasmic domain of CTLA-4. Since it is clear that the present study more closely reflects physiological function than the previous study, the obvious requirement of the cytoplasmic domain of CTLA-4 for its inhibitory function may suggest the importance of the assembly of the CTLA-4 tail with inhibitory molecules including SHP-2 [18,20] or regulatory molecules such as PP2A [22,23]. Further studies are needed to clarify the in vivo inhibitory mechanism through CTLA-4 in different stages of T cell development.…”

Section: Discussionmentioning

confidence: 63%

“…Although it has been suggested that several molecules, such as Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2) and phosphatidyl inositol 3-kinase (PI3K), may mediate the negative signal through binding to the phosphorylated tyrosine motif (YVKM) present in the cytoplasmic region of CTLA-4 [18][19][20], the precise inhibitory mechanism remains controversial [21][22][23]. We and others have previously shown that the PI3K/ SHP-2 binding sites are not essential for CTLA-4-mediated inhibitory signals in T cell clones/cell lines [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

et al. 2005

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Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) induces major inhibitory signals for T cell activation. From analyses of TCR‐transgenic (Tg) CTLA‐4‐deficient mice, it has been believed that CTLA‐4 does not affect thymocyte development. To focus upon the in vivo function of CTLA‐4 in thymocyte development from a different aspect, we have established Tg mice expressing either full‐length CTLA‐4 (FL‐Tg) or a mutant CTLA‐4 lacking the cytoplasmic region (truncated, TR‐Tg), and analyzed thymocyte development. TR‐T cells express much higher CTLA‐4 on the cell surface than FL‐T cells, in which most CTLA‐4 was localized in intracellular vesicles. While CTLA‐4–/– mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA‐4–/– background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double‐positive thymocytes by injection of anti‐CD3 Ab as well as the elimination of minor lymphocyte‐stimulating antigen‐reactive thymocytes were impaired in FL‐Tg mice but not in TR‐Tg mice. Functionally, cross‐linking of CTLA‐4 on thymocytes from FL‐Tg mice, but not from TR‐Tg mice, inhibited proliferation. These results reveal a potential role of CTLA‐4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

et al. 2005

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“…We suggest that the significantly lower CD28 antigen expression on both subsets of unstimulated T cells and its more profound and long-lasting downregulation after stimulation compared with normal controls as observed in our study may deliver a stronger and prolonged stimulus for CD152 induction and expression on the CD3 þ / CD4 þ and CD3 þ /CD8 þ T-cell subpopulations in B-CLL. Since CD152 inhibits T-cell responses, increased expression of CD152 molecule on both subsets of T cells may result in an impairment of T-cell function in patients with B-CLL (Bartik et al, 1998;Lee et al, 1998;Metzler et al, 1999;Carreno et al, 2000;Frydecka et al, 2003;Wolowiec et al, 2003). This hypothesis was confirmed by our previously reported results, which showed strong negative correlations between the proportion of PB CD3 þ / CD152 þ cells and proliferative activity, IL-2 and IFN-g production in patients with Hodgkin's disease and healthy subjects .…”

Section: Discussionmentioning

confidence: 99%

Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia

et al. 2004

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In the present study, we have examined the kinetics and magnitude of expression of the CD28 and CD152 molecules on unstimulated and anti-CD3 þ rIL-2-stimulated peripheral blood CD4 þ and CD8 þ T cells in patients with chronic lymphocytic leukaemia (B-CLL) and controls. The mean percentages of both CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ /CD28 þ cells were significantly lower in B-CLL than in controls before culture, decreased rapidly, reaching their lowest levels between 24 and 48 h, and returned to basal levels after 72 h of culture. In controls, the lowest proportions of CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ / CD28 þ cells were found after 24 h and returned to prestimulation levels after 48 h of stimulation. We observed significantly higher proportions of unstimulated CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells in B-CLL patients than in controls. The highest percentages of CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells were observed in controls after 72 h, and in B-CLL patients after 24 h, and remained statistically higher after 48, 72 and 96 h of stimulation. CD152 molecule expression returned to prestimulation levels after 96 h of culture in controls, and after 120 h in B-CLL patients. The abnormal kinetics and levels of CD28 and CD152 expression on T cells in B-CLL may lead to a state of hyporesponsiveness or anergy and could be one of the mechanisms of immune deficiency in this disease.

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“…It has been described earlier that SHP-2 is able to interact directly or indirectly with the inhibitory coreceptor CTLA-4 (CD152) [22][23][24][25]. For this reason, transduced T cells were re-stimulated with anti-CD3 and anti-CD28 or anti-CD3, anti-CD28 and anti-CTLA4 coupled to microspheres to induce either no or a strong CTLA-4 signal.…”

Section: Activation and Proliferation Are Intact In Individual T Lympmentioning

confidence: 99%

“…On the other hand, SHP-2 has been attributed to relay the inhibitory signals from over-expressed Gab2 [20], although other results show that instead PI3K is mediating this inhibitory effect [21]. Additionally, SHP-2 can be co-precipitated with the inhibitory coreceptor CTLA-4 (CD152) and CD3-f, which has led to the hypothesis that SHP-2 mediates inhibitory signals from CTLA-4 [22][23][24][25]. Furthermore, other inhibitory molecules, such as PD-1 and BTLA, containing the canonical ITIM as well as ITSM motifs were shown to recruit SHP-2 in a phosphorylation-dependent manner [26,27].…”

Section: Introductionmentioning

confidence: 99%

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

Hoff

Brunner‐Weinzierl

2007

Eur J Immunol

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Although phosphatases are key players of intracellular processes, not much is known about the phosphatase SHP-2 during T cell differentiation. Here we show that ectopic over-expression of SHP-2 in primary T helper cells directly reduced the frequency of individual lymphocytes expressing pro-inflammatory cytokines after antigen-specific stimulation by a mechanism impairing activation of protein kinase C. In addition we demonstrate that SHP-2 mediates enhanced migration upon CXCR4 signaling in a G-protein-dependent manner. Most strikingly, SHP-2 mediated a dramatic increase in apoptosis by highly enhanced activation of caspases. Co-immunoprecipitations of SHP-2 and c-Cbl from primary T helper cells demonstrated that SHP-2 strongly interacts with the ubiquitin ligase c-Cbl, indicating that c-Cbl could mediate the negative signals of SHP-2. Our results show that SHP-2 signal transduction regulates central checkpoints of T cell differentiation by the activation of distinct signaling cascades.

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Molecular Basis of T Cell Inactivation by CTLA-4

Cited by 618 publications

References 28 publications

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

Alterations of the expression of T-cell-related costimulatory CD28 and downregulatory CD152 (CTLA-4) molecules in patients with B-cell chronic lymphocytic leukaemia

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

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