Differential requirement of PKC-θ in the development and function of natural regulatory T cells

Gupta, Sonal; Manicassamy, Santhakumar; Vasu, Chenthamarakshan; Kumar, Anvita; Shang, Weirong; Sun, Zuoming

doi:10.1016/j.molimm.2008.08.275

Cited by 125 publications

(123 citation statements)

References 64 publications

(98 reference statements)

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“…Thus, although c-Rel is required for the presence of normal numbers of Treg, neither p50 nor c-Rel is required for Treg to exert their suppressor activity. This is consistent with the finding that neither PKCy nor CARMA-1 are required for Treg function [13,14] and suggests that Treg function and generation are controlled by separate signalling pathways.…”

Section: Cd25supporting

confidence: 91%

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c‐Rel but not NF‐κB1 is important for T regulatory cell development

et al. 2010

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Regulatory T (Treg) cells are crucial for maintaining peripheral tolerance and controlling T-cell responses. The generation of Treg in the thymus requires TCR triggering and CD28 costimulation. Engagement of these receptors induces a number of signalling pathways, including the activation of NF-jB via PKCh and the Bcl-10/CARMA1/MALT complex. Previous studies have shown that PKCh, Bcl-10 and CARMA1 are important for Treg development. It is unclear, however, whether different members of the NF-jB family contribute to Treg development or homeostasis. In this study, we show that Treg numbers are reduced in the absence of c-Rel but not NF-jB1 (p50). Furthermore, using mixed bone marrow chimeras from WT and KO animals, we demonstrate that the requirement for PKCh, Bcl-10 and c-Rel is T-cell intrinsic, and cannot be rescued by the presence of WT cells. Therefore, c-Rel and NF-jB1 have differential roles in Treg development.

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Section: Cd25supporting

confidence: 91%

“…Consistent with this, mice deficient in PKCy [12,13], Bcl-10 [12], CARMA-1 [14][15][16] or IKK2 [17] also show a decrease in the number of Treg both in the thymus and in the periphery.…”

Section: Introductionsupporting

confidence: 55%

c‐Rel but not NF‐κB1 is important for T regulatory cell development

et al. 2010

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“…For example, individuals with functional defects in STIM or Ca 2ϩ release-activated Ca 2ϩ /Orai are profoundly immune-deficient, and mice conditionally lacking STIM in T lymphocytes develop autoreactive disorders in part because of defective thymic natural regulatory T cell induction by highaffinity self-agonists (70). A similar and selective defect in natural regulatory T cell development occurs in mice selectively lacking either c-Rel (71)(72)(73)(74)(75)(76) or upstream mediators of NF-B activation, including BCL10, PKC, CARMA1, CnA␤, and IKK␤ (77)(78)(79)(80)(81). Although our study focuses on p65-dependent transcriptional activation, the dual sensitivity of proximal and distal Ca 2ϩ signals we identified and the role of c-Rel in natural regulatory T cell development raises the intriguing possibility that c-Rel transcriptional activation is also Ca 2ϩ -dependent.…”

Section: Discussionmentioning

confidence: 98%

T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

Liu

Berry

Ruthel

et al. 2016

Journal of Biological Chemistry

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T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca2؉ to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-B. 2؉ -dependent checkpoint in TCR-induced NF-B signaling that has broad implications for the control of immune cell development and T cell functional specificity. Activation of T cells following antigen binding to the T cell antigen receptor (TCR)3 induces diverse lineage-and fate-specific proinflammatory and immune-modulatory responses. Central to these responses is the induction of quantitatively distinct intracellular Ca 2ϩ signals and their selective activation of the key transcription factors NFAT and NF-B (1-6). The mechanism by which Ca 2ϩ controls NFAT activation in lymphocytes is well established (7). In contrast, although Ca 2ϩ has been implicated in TCR-induced NF-B signaling (8 -10), how Ca 2ϩ regulates NF-B activity is largely unexplored and represents a significant gap in our understanding of transcriptional control of T cell development, activation, and functional specificity.In resting T cells, classical NF-B consists of heterodimers of p50/p65 or p50/c-Rel that are retained in the cytosol by members of the inhibitory family of IB proteins (11, 12). Following TCR engagement, IB kinase (IKK)-mediated phosphorylation triggers the ubiquitination and proteasomal degradation of IB␣, releasing p50/p65 and p50/c-Rel, which localize to the nucleus to initiate transcription of crucial immune-regulatory, proinflammatory, and proproliferative genes (13-30). Although TCR-mediated Ca 2ϩ mobilization has been implicated in proximal steps of NF-B activation (8 -10), the precise mechanisms and source of Ca 2ϩ that regulate nuclear localization and transcriptional activation of NF-B are poorly defined. It is well established that TCR signaling induces inositol 1,4,5-trisphosphate-mediated depletion of Ca 2ϩ from the endoplasmic reticulum (ER). A resulting Ca 2ϩ dissociation from the ER membrane protein stromal interaction molecule 1 (STIM1) triggers its oligomerization and relocalization to ER membrane domains juxtaposed to the plasma membrane (31-33), where STIM1 physically gates Orai (also known as Ca 2ϩ release-activated Ca 2ϩ ) channels, allowing extracellular Ca 2ϩ to enter the cell (34,35). However, it is not known whether Ca 2ϩ control of TCR-induced NF-B signaling requires STIM1-and Orai1-mediated Ca 2ϩ influx or whether the initial release of Ca 2ϩ from the ER is sufficient for classical NF-B activation.In this study, we sought to determine both the source and mechanism of Ca 2ϩ control of antigen receptor-induced NF-B activation in T cells. We show that influx of extracellular Ca 2ϩ via STIM1 and Orai is critical for TCR-but not TNFinduced IB␣ degradation and NF-B activation. Importantly, we also demonstrate that Ca 2ϩ -dependent, PKC␣-mediated phosphorylation of p65 critically regulates its nuclear localization and transcriptional activation following TCR engagement. Thus, our findings ...

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“…Tregs can suppress GVHD induction (47). In contrast to conventional T cells, PKCθ is required for the development of Tregs in the thymus but dispensable for their suppressive function (48). To exclude the contribution of Tregs, e.g., because of differences in Treg numbers between WT and PKCθ -/-mice, we removed Tregs (CD4 + CD25 + ) from donor T cell populations in our studies.…”

Section: Discussionmentioning

confidence: 99%

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Valenzuela¹,

Iclozan²,

Hossain³

et al. 2009

J. Clin. Invest.

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When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graftversus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform θ (PKCθ), a key regulator of TCR signaling. In contrast, PKCθ was required for alloreactivity and GVHD induction. Furthermore, absence of PKCθ raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCθ-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCθ is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.

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Differential requirement of PKC-θ in the development and function of natural regulatory T cells

Cited by 125 publications

References 64 publications

c‐Rel but not NF‐κB1 is important for T regulatory cell development

c‐Rel but not NF‐κB1 is important for T regulatory cell development

T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

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