Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells

Chambers, Cynthia A.; Sullivan, Timothy J.; Truong, Thien; Allison, James P.

doi:10.1002/(sici)1521-4141(199810)28:10<3137::aid-immu3137>3.0.co;2-x

Cited by 111 publications

(20 citation statements)

References 34 publications

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“…For instance, antibodies that activate CD40 on APCs upregulate co-stimulatory molecules that help facilitate priming of naïve cells (25–27). In contrast, antibodies that block the T cell inhibitory cell surface molecule CTLA-4 minimally impact naïve T cells but significantly enhance proliferation and effector function of primed T cells (28,29). Inhibition of proteins that negatively regulate signal transduction downstream of the TCR has garnered recent attention as a potential strategy for augmenting T cell responses to malignancy at the time of T cell priming.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases

et al. 2013

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Recent clinical trials have shown promise in the use of chimeric antigen receptor(CAR)-transduced T cells; however, augmentation of their activity may broaden their clinical utility and improve their efficacy. We hypothesized that, since CAR action requires proteins essential for TCR signal transduction, deletion of negative regulators of these signaling pathways would enhance CAR signaling and effector T cell function. We tested CAR activity and function in T cells that lacked one or both isoforms of diacylglycerol kinase (dgk) expressed highly in T cells, dgkα and dgkζ, enzymes that metabolize the second messenger diacylglycerol (DAG) and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin demonstrated greatly enhanced cytokine production and cytotoxicity when co-cultured with a murine mesothelioma line that stably expresses mesothelin. Additionally, we found that dgk-deficient CAR-transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. Consistent with our studies in mice, pharmacologic inhibition of dgks also augments function of primary human T cells transduced with CARs. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells and identify dgks as potential targets for improving the clinical potential of CARs.

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Section: Discussionmentioning

confidence: 99%

Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases

et al. 2013

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“…In support of this model, conventional CD4+ and CD8+ cells that do not express CTLA-4 have a higher proliferative capacity in vitro and in vivo. 15, 31–35 The cell extrinsic activity of CTLA-4 on immune response, focusing on a role for Tregs, has been more challenging to define. Early experiments demonstrating that CTLA-4 −/− T cells transferred into RAG ½ −/− hosts could be inhibited by concomitant transfer of WT T cells suggested trans -regulation by CTLA-4 sufficient WT cells36, 37, later defined as a CD4+CD25+ Tregs 38.…”

Section: Ctla-4 Mechanism(s) Of Actionmentioning

confidence: 99%

Anti–CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development of a Novel Immunotherapy

Callahan

Wolchok

Allison

2010

Seminars in Oncology

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213

157

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Cytotoxic T lymphocyte-associated antigen (CTLA-4), also known as CD152, is a co-inhibitory molecule that functions to regulate T cell activation. Antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including anti-tumor immunity. Two CTLA-4 blocking antibodies are presently under clinical investigation: ipilimumab and tremelimumab. CTLA-4 blockade has shown promise in treatment of patients with metastatic melanoma, with a recently completed randomized, double-blind Phase III trial demonstrating a benefit in overall survival (OS) in the treated population. However, this approach appears to benefit only a subset of patients. Understanding the mechanism(s) of action of CTLA-4 blockade and identifying prognostic immunologic correlates of clinical endpoints to monitor are presently areas of intense investigation. Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed.

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“…Importantly, because CTLA‐4 is not expressed until relatively late following T‐cell activation, its ability to deliver negative signals may be delayed until after the onset of cell division. Consistently, it has proved somewhat difficult to demonstrate inhibition of T‐cell proliferation by CTLA‐4 during primary T‐cell responses (70), especially using natural ligands. Thus, the concept of CTLA‐4 as an ‘off switch’ that prevents initial T‐cell proliferation seems less likely, although it may act as a brake following CTLA‐4 induction upon cell division (71).…”

Section: Mechanisms Of Cd28 and Ctla‐4 Functionmentioning

confidence: 99%

The role of CD28 and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) in regulatory T‐cell biology

Sansom

Walker

2006

Immunological Reviews

261

200

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The profound influence of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T-cell immunity has been known for over a decade, yet the precise roles played by these molecules still continue to emerge. Initially viewed as molecules that provide cell-intrinsic costimulatory and inhibitory signals, recent evidence suggests that both CD28 and CTLA-4 are also important in the homeostasis and function of a population of suppressive cells, termed regulatory T cells (Tregs). Here we review the main features of the CD28 and CTLA-4 system and examine how these impact upon Treg biology.

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Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells

Cited by 111 publications

References 34 publications

Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases

Enhanced Effector Responses in Activated CD8+ T Cells Deficient in Diacylglycerol Kinases

Anti–CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development of a Novel Immunotherapy

The role of CD28 and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) in regulatory T‐cell biology

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