CTLA-4 Control over Foxp3
            <sup>+</sup>
            Regulatory T Cell Function

Wing, Kajsa; Onishi, Yasushi; Prieto-Martin, Paz; Yamaguchi, Tomoyuki; Miyara, Makoto; Fehérvari, Zoltán; Nomura, Takashi; Sakaguchi, Shimon

doi:10.1126/science.1160062

Cited by 2,553 publications

(2,314 citation statements)

References 25 publications

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“…Continuous TCR signalling and CTLA4 expression are required for the suppressive function of Treg cells 17, 18, 24. Consistent with the finding that deletion of Pak2 decreased expression of CTLA4 in CD25 + Foxp3 + Treg cells and the cell proliferation (Fig.…”

Section: Discussionsupporting

confidence: 88%

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

et al. 2018

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SummaryThe p21‐activated kinase 2 (Pak2), an effector molecule of the Rho family GTPases Rac and Cdc42, regulates diverse functions of T cells. Previously, we showed that Pak2 is required for development and maturation of T cells in the thymus, including thymus‐derived regulatory T (Treg) cells. However, whether Pak2 is required for the functions of various subsets of peripheral T cells, such as naive CD4 and helper T‐cell subsets including Foxp3+ Treg cells, is unknown. To determine the role of Pak2 in CD4 T cells in the periphery, we generated inducible Pak2 knockout (KO) mice, in which Pak2 was deleted in CD4 T cells acutely by administration of tamoxifen. Temporal deletion of Pak2 greatly reduced the number of Foxp3+ Treg cells, while minimally affecting the homeostasis of naive CD4 T cells. Pak2 was required for proliferation and Foxp3 expression of Foxp3+ Treg cells upon T‐cell receptor and interleukin‐2 stimulation, differentiation of in vitro induced Treg cells, and activation of naive CD4 T cells. Together, Pak2 is essential in maintaining the peripheral Treg cell pool by providing proliferation and maintenance signals to Foxp3+ Treg cells.

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Section: Discussionsupporting

confidence: 88%

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

et al. 2018

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“…Treg can interact with other immune populations via soluble factors and/or via cell-contactdependent mechanisms. Whereas in vivo studies have suggested a major role for soluble factors, such as IL-10 [41], TGF-b [42], or IL-35 [43], most in vitro experiments described a cell-contactdependent mechanism, involving CTLA-4 [44,45], GITR [46], Perforin [33], or Granzyme B [34]. Our data suggest that Perforin/ Granzyme-induced apoptosis does not play a major role in Tregmediated suppression of mouse gd-T-cell activity.…”

Section: Discussionmentioning

confidence: 51%

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

et al. 2009

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cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

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“…This suggests that CTLA-4 controls TCR accumulation/retention in membrane microdomains thereby blocking formation of a stable immunological synapse and downstream signalling events. In addition, CTLA-4 is constitutively expressed on the majority of Treg, and plays an important role in their function [9][10][11][12]. The relative contribution of CTLA-4 to the intrinsic regulation of responder T-cell activation and Treg function remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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CTLA-4 Control over Foxp3 ⁺ Regulatory T Cell Function

Cited by 2,553 publications

References 25 publications

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

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CTLA-4 Control over Foxp3 + Regulatory T Cell Function

Cited by 2,553 publications

References 25 publications

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3+ regulatory T cells

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3+ regulatory T cells

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

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CTLA-4 Control over Foxp3 ⁺ Regulatory T Cell Function

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells