Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+ Regulatory T Cells

Karman, Jozsef; Jiang, Ji-Lei; Gumlaw, Nathan; Zhao, Hongmei; Campos‐Rivera, Juanita; Sancho, José; Zhang, Jinhua; Jiang, Canwen; Cheng, Seng H.; Zhu, Yunxiang

doi:10.1074/jbc.m111.283705

Cited by 24 publications

(25 citation statements)

References 49 publications

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“…It is likely that cross-linking mCTLA-4 provides an agonist signal to the T cell, stimulating cell-intrinsic inhibitory signaling mediated via its cytoplasmic domain. Indeed, there is good evidence that cell extrinsic regulatory effects of CTLA-4 can be mediated solely through the extracellular B7 binding domain of the molecule [45]. For example, recombinant soluble CTLA4-Ig, a fusion of the CTLA-4 extracellular domain with immunoglobulin has been shown to rescue CTLA-4 −/− mice from fatal lymphoproliferative disease [46] and to induce APC regulatory mechanisms such as induction of the T-cell inhibitory IDO enzyme [17].…”

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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“…CTLA-4 regulates T cells predominantly during initial activation by dendritic cells and other APCs (priming phase; refs. [13][14][15]. Furthermore, CTLA-4 is expressed by regulatory T cells (Treg) and memory CD4 cells and these cells may also be targeted by CTLA-4 blockade (16).…”

Section: Introductionmentioning

confidence: 99%

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

Ott

Hodi

Robert

2013

Clinical Cancer Research

609

455

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Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAF V600 -mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials.Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies.

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“…The cytotoxic T-lymphocyte associated protein 4 gene (CTLA-4), on chromosome 2q33, has been shown to be a negative regulator of T-cell activation during immune response (Kosmaczewska et al, 2001;Karman et al, 2012). The protein tyrosine phosphatase, nonreceptor type 22 (lymphoid) gene (PTPN22), on chromosome 1p13.2, encodes the lymphoidspecific phosphatase (Lyp) and is involved in the prevention of spontaneous T-cell activation (Vang et al, 2007;Burn et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Association of TNF-α, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil

Tavares¹,

Santos²,

Moura³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Type 1 diabetes mellitus (T1D) is a complex disorder characterized by an autoimmune response against human pancreatic beta-cells. Patients with T1D can also develop a response toward one or more other factors, such as in autoimmune thyroiditis (AITD) and celiac disease (CD). In the presence of T1D + AITD, the patient is diagnosed with autoimmune polyglandular syndrome type III (APSIII); patients with APSIII may also present with CD. These diseases have a strong genetic component and share many susceptibility genes, suggesting potentially overlapping pathogenic pathways. Polymorphisms in the TNF-α (rs1800629), CTLA-4 (rs231775), and PTPN22 (rs2476601) genes have been previous associated with T1D; however, there is no consensus regarding their role in T1D and scarce literature focusing on AIDT and/or CD. Thus, we analyzed these genetic variants in 205 Northeast Brazilian patients with T1D and with/without AITD and/or CD, and in 308 healthy controls. The PTPN22 gene variants were associated with T1D susceptibility and APSIII [odds ratio (OR) = 2.57 and 2.77, respectively]. CTLA4 rs231775 and TNF-α rs1800629 were not associated with T1D onset in the Brazilian population. However, when comparing APSIII individuals in the T1D only group, we observed an association of the TNF-α SNP in the allelic (P = 0.0442; OR = 0.44) and dominant models (P = 0.0387; OR = 0.40). This study reinforces the importance of CTLA-4 and other variants in unraveling the pathogenic mechanisms of T1D in different populations and in understanding their relationships with the development of other T1D-related autoimmune diseases.

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Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+ Regulatory T Cells

Cited by 24 publications

References 49 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

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

Association of TNF-α, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil

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