T-cell regulation by CD28 and CTLA-4

Alegre, Maria‐Luisa; Frauwirth, Kenneth A.; Thompson, Craig B.

doi:10.1038/35105024

Cited by 754 publications

(673 citation statements)

References 98 publications

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“…Resting T cells require signals from the T cell receptor (TCR) or the interleukin-7 receptor (IL-7R) to prevent death-by-neglect both in vivo and in vitro [7][8][9][10]. During T cell activation, signals from the TCR and the costimulatory molecule CD28 are required to stimulate maximal cell survival and proliferation [11]. If costimulation through CD28 is not available, TCR signals fail to lead to significant cell proliferation and can instead lead to cell death [12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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“…CTLA-4 is a major costimulatory receptor that negatively regulates T cell activation [1][2][3][4]. CTLA-4 has a homologous structure to CD28 and binds to the same ligands, CD80/CD86, as CD28, but with much higher affinity.…”

Section: Introductionmentioning

confidence: 99%

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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“…Among a variety of inhibitory pathways, attention has focused on CTLA-4, an immunoglobulin superfamily member that plays a key role in restraining T cell responses [1, 2]. Common single nucleotide polymorphisms (SNP) in CTLA4 have been associated with disease susceptibility and outcome in autoimmune diseases and viral hepatitis, respectively [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, CD4 + CD25 + T cells (Treg) have also been shown to play a central role in restraining the vigor of immune responses to pathogens [8][9][10][11][12][13][14][15]. While CTLA-4 was classically thought to restrain T cell responses by acting in cis on activated T cells [1], it has become clear that CTLA-4 can also act in trans [16,17]. Notably, Treg constitutively express CTLA-4, and Treg-mediated inhibition of T cell responses is due to CTLA-4 in a variety of experimental systems [6, 7,[18][19][20][21][22][23].…”

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confidence: 99%

Association ofCTLA4 polymorphism with regulatory T cell frequency

et al. 2005

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A common single nucleotide polymorphism in CTLA4 has been linked with susceptibility and outcome in autoimmune and infectious diseases, respectively. Here, we show that this polymorphism is associated with the frequency of CD4 + CD25 + regulatory T cells in healthy human volunteers. We further show that, on a per cell basis, such regulatory T cells appear to be functionally indistinguishable across CTLA4 genotypes. These data implicate CTLA4 in regulatory T cell development, and provide a mechanism to account for the link between polymorphisms at this locus and the biological outcome of adaptive immune responses to self and to pathogens. IntroductionInhibition is as important as activation in regulating the vigor of immune responses. Among a variety of inhibitory pathways, attention has focused on CTLA-4, an immunoglobulin superfamily member that plays a key role in restraining T cell responses [1, 2]. Common single nucleotide polymorphisms (SNP) in CTLA4 have been associated with disease susceptibility and outcome in autoimmune diseases and viral hepatitis, respectively [3][4][5]. CTLA4 alleles associated with increased susceptibility to autoimmune disease are also associated with increased clearance of hepatitis B virus infection; similarly alleles associated with protection from autoimmune disease are also associated with reduced clearance of hepatitis B virus infection [4, 5]. Such associations have biological plausibility: decreasing the vigor of T cell responses would be expected to decrease susceptibility to tissue-destructive autoimmune processes as well as to decrease the likelihood of clearing viral infection.The field of immune regulation has been revolutionized by the recent identification of a specialized population of suppressor CD4 + T cells [6, 7]. Characterized phenotypically by constitutive expression of IL-2Ra (CD25), these cells were first identified by their role in maintaining self tolerance. Subsequently, CD4 + CD25 + T cells (Treg) have also been shown to play a central role in restraining the vigor of immune responses to pathogens [8][9][10][11][12][13][14][15]. While CTLA-4 was classically thought to restrain T cell responses by acting in cis on activated T cells [1], it has become clear that CTLA-4 can also act in trans [16,17]. Notably, Treg constitutively express CTLA-4, and Treg-mediated inhibition of T cell responses is due to CTLA-4 in a variety of experimental systems [6, 7,[18][19][20][21][22][23]. In addition to being part of the effector armamentarium of Treg, however, data from mouse models are compatible with a role for CTLA-4 in Treg development [23,24]. We thus hypothesized an influence of CTLA4 polymorphisms on Treg development. (Fig. 1a).No such correlation of genotype and Treg frequency was found for another well-characterized polymorphism (+49; exon 1) in CTLA4 (Fig. 1b). Of interest, this latter polymorphism is in linkage disequilibrium with the CT60 SNP. All volunteers homozygous for the A allele at CT60 were also homozygous for the A allele at +49, but the reverse ...

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T-cell regulation by CD28 and CTLA-4

Cited by 754 publications

References 98 publications

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

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

Association ofCTLA4 polymorphism with regulatory T cell frequency

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