Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells

Manzotti, Claire N.; Tipping, Helen; Perry, Laura C. A.; Mead, Karen I.; Blair, Patrick J.; Zheng, Yong; Sansom, David M.

doi:10.1002/1521-4141(2002010)32:10<2888::aid-immu2888>3.0.co;2-f

Cited by 123 publications

(88 citation statements)

References 44 publications

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“…Cell extrinsic regulation by CTLA-4 has been strongly linked to Treg-cell populations, with increased levels of CTLA-4 message in Treg cells relative to other CD4 + T-cell types, and CTLA-4 expression required for effective Treg-cell function [11][12][13][14][15]19]. Analyses of CTLA-4 levels in Treg cells have previously been limited to methods that do not discriminate between the isoforms, with the assumption that all the CTLA-4 detected, and thus all of the regulatory function mediated by it, arises solely from the receptor isoform of the molecule.…”

Section: Discussionmentioning

confidence: 99%

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

et al. 2013

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CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses.Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity. Keywords: CD4 + T cells r Costimulatory molecules r Immune regulation r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Introduction CTLA-4 is an important regulator of T-cell responses [1][2][3][4]. Its critical role is highlighted by CTLA-4 knockout mice, which develop a fatal lymphoproliferative disorder soon after birth, arising from a profound failure of T-cell homeostasis [5,6]. Despite these potent effects, the activities of CTLA-4 are only partially understood.CTLA-4 shares sequence homology and B7 ligands (CD80/CD86) with the costimulatory molecule, CD28, but differs by delivering inhibitory, rather than activating, signals to the T cells on which it is expressed as a receptor [7,8]. Upregulation of CTLA-4 on activated T cells provides a mechanism for negative Correspondence: Dr. Frank J. Ward e-mail: mmd475@abdn.ac.uk feedback to control their responses. However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9,10]. This latter, cell-extrinsic mechanism has been largely attributed to CD4 + regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, and require it for their regulatory function [11][12][13][14][15][16].How Treg cells might use CTLA-4 to regulate effector T-cell responses remains controversial. It has been suggested that CTLA-4 on Treg cells binds B7 and thus blocks CD28-mediated effector T-cell costimulation, or that it induces inhibitory mechanisms in the APC such as the IDO tryptophan catabolic enzyme * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1274-1285 Immunomodulation 1275 cas...

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Section: Discussionmentioning

confidence: 99%

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

et al. 2013

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“…We postulate that this suppression is mediated by similar mechanisms that were described previously in other non-HIV regulatory T cell populations. Suppression may occur through direct binding of inhibitory cell surface molecules such as CTLA-4 to costimulatory molecules (including CD80 and CD86) on effector T cells (43,44). These HIV-specific suppressor CD8 ϩ T cells may also recognize MHC peptide complexes on the cell surface of APCs, triggering the up-regulation of the inhibitory receptors Iglike transcripts (ILT)3 and ILT4 and the down-regulation of costimulatory molecules rendering the APC tolerogenic (33,45,46).…”

Section: Discussionmentioning

confidence: 99%

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

Elrefaei

Ventura

Baker

et al. 2007

The Journal of Immunology

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IL-10 producing T cells inhibit Ag-specific CD8+ T cell responses and may play a role in the immune dysregulation observed in HIV infection. We have previously observed the presence of HIV-specific IL-10-positive CD8+ T cells in advanced HIV disease. In this study, we examined the suppressive function of the Gag-specific IL-10-positive CD8+ T cells. Removal of these IL-10-positive CD8+ T cells resulted in increased cytolysis and IL-2, but not IFN-γ, production by both HIV- and human CMV-specific CD8+ T cells. In addition, these IL-10-positive CD8+ T cells mediated suppression through direct cell-cell contact, and had a distinct immunophenotypic profile compared with other regulatory T cells. We describe a new suppressor CD8+ T cell population in advanced HIV infection that may contribute to the immune dysfunction observed in HIV infection.

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“…Peripheral blood T cells were obtained from buffy coat preparations supplied by the National Blood Transfusion Service and were isolated as described in Ref. 31. Isolated peripheral blood T cells were used directly after isolation (quiescent cells) or were activated with 2 ng/ml phorbol 12-myristate 13-acetate and 1 g/ml ionomycin for 72 h.…”

Section: Methodsmentioning

confidence: 99%

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Stokes¹,

Gordon²,

Grafton

2004

Journal of Biological Chemistry

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In T lymphocytes, engagement of the antigen receptor leads to a biphasic Ca 2؉ flux consisting of a mobilization of Ca 2؉ from intracellular stores followed by a lower but sustained elevation that is dependent on extracellular Ca 2؉ . The prolonged Ca 2؉ flux is required for activation of transcription factors and for subsequent activation of the T cell. Ca 2؉ influx requires as yet unidentified Ca 2؉ channels, which potentially play a role in T cell activation. Here we present evidence that human T cells express a non-voltage-gated Ca 2؉ channel related to L-type voltage-gated Ca 2؉ channels. Drugs that block classical L-type channels inhibited the initial phase of the antigen receptor-induced Ca 2؉ flux and could also inhibit the sustained phase of the Ca 2؉ signal suggesting a role for the L-type Ca 2؉ channel in antigen receptor signaling. T cells expressed transcripts for the ␣ 1 1.2 and ␣ 1 1.3 pore-forming subunits of L-type voltage-gated Ca 2؉ channels and transcripts for all four known ␤-subunits including several potential new splice variants. Jurkat T leukemia cells expressed a small amount of full-length ␣ 1 1.2 protein but the dominant form was a truncated protein identical in size to a truncated ␣ 1 1.2 protein known to be expressed in B lymphocytes. They further expressed a truncated form of the ␣ 1 1.3 subunit and auxiliary ␤1-and ␤3-subunit proteins. Our data strongly suggest that functional but non-voltage-gated L-type Ca 2؉ channels are expressed at the plasma membrane in T cells and play a role in the antigen receptor-mediated Ca 2؉ flux in these cells.

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Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells

Cited by 123 publications

References 44 publications

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

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