CD4+ and CD8+ T Cell Survival Is Regulated Differentially by Protein Kinase Cθ, c-Rel, and Protein Kinase B

Saibil, Samuel D.; Jones, Russell G.; Deenick, Elissa K.; Liadis, Nicole; Elford, Alisha R.; Vainberg, Mitchell G.; Baerg, Heather; Woodgett, James R.; Gerondakis, Steve; Ohashi, Pamela S.

doi:10.4049/jimmunol.178.5.2932

Cited by 47 publications

(42 citation statements)

References 70 publications

(65 reference statements)

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“…18 However, after PbA infection, analysis of brain-sequestered cells clearly showed a sharp reduction in brain-infiltrating CD4 ϩ , and more drastically of CD8 ϩ and CD8 ϩ CD69 ϩ T cells in CM-resistant PKC--deficient mice. These results are in agreement with those of Saibil et al, 44 who observed that the absence of PKCstrongly affected the primary activated CD8 ϩ T cells, whereas CD4 ϩ T cells exhibited only a moderate survival defect. Immunohistologic analysis confirmed reduced recruitment and activation of CD4 ϩ and CD8 ϩ T cells in the brains of PKC--deficient mice.…”

Section: Discussionsupporting

confidence: 93%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-) in experimental CM development was examined. PKC--deficient mice are resistant to CM development. In the absence of PKC-, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC--deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8 ؉ T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-. Resistant PKC--deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-signaling is crucial for recruitment of CD8 ؉ T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.

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Section: Discussionsupporting

confidence: 93%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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“…Previous studies including ours have shown that protein kinase C (PKC-) regulates the Ca 2ϩ /NFAT pathway (18 -20) as well as T cell survival (16,21,22); we thus intended to determine whether Cn plays a role in PKC--regulated T cell survival. Mice deficient in catalytic subunit A␤ (CnA␤ Ϫ/Ϫ ) were used in this study because, similar to PKC-, CnA␤ also mediates TCR signals required for T cell activation (4).…”

Section: ϫ/ϫ T Cells Undergo Accelerated Spontaneous Apoptosismentioning

confidence: 99%

Requirement of Calcineurin Aβ for the Survival of Naive T Cells

Manicassamy

Gupta

Huang

et al. 2008

The Journal of Immunology

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Calcineurin (Cn) is a Ca2+/calmodulin-dependent phosphatase that dephosphorylates and activates NFAT, a transcription factor essential for T cell activation. T lymphocytes predominantly express the calcineurin Aβ (CnAβ) isoform, and the deletion of the CnAβ gene results in defective T cell proliferation and IL-2 production in response to TCR stimulation. In this study, we show that CnAβ enhances the spontaneous survival of naive T cells by maintaining high levels of Bcl-2, a critical homeostatic survival factor for naive T cells. T cells obtained from CnAβ−/− mice displayed accelerated spontaneous apoptosis. The observed apoptosis of the CnAβ−/− T cells was prevented by IL-7 and IL-15, two cytokines critical for the homeostatic survival of naive T cells. Furthermore, CD4+ or CD8+ single positive CnAβ−/− thymocytes also underwent accelerated apoptosis. However, no obvious difference in the apoptosis of CD4+CD8+ double positive thymocytes was observed between CnAβ−/− and wild-type mice, suggesting a specific function of CnAβ in the survival of single positive T cells. Bcl-2 levels were found to be significantly lower in CnAβ−/− T cells. Transgenic expression of Bcl-xL restored the survival of the CnAβ−/− T cells. Thus, in addition to its role in mediating TCR signals essential for T cell activation, CnAβ is also required for the homeostatic survival of naive T cells.

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“…Several recent reports have supported a role for PKCy and c-Rel in survival via induction of Bcl-X L [30][31][32]. Thus, c-Rel may also play a role in regulating peripheral tolerance by controlling survival versus elimination of potentially self-reactive cells.…”

Section: The Induction Of Anergy Is Not a Consequence Of Impaired Surmentioning

confidence: 99%

“…It has recently been shown that signaling through PKCy leads to the induction of Bcl-X L [30,31] and that this upregulation of Bcl-X L is dependent on c-Rel but is independent of p50 [32]. Furthermore, overexpression of Bcl-X L prevents the induction of tolerance in several transplantation models [33,34].…”

Section: Bcl-x L Does Not Restore T-cell Functionmentioning

confidence: 99%

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance

Deenick

Chapatte

et al. 2010

Eur J Immunol

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Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCh results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-jB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-jB act downstream of PKCh to alter CD8 1 T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-jB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCh-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCh-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-jB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCh in controlling CD81 T-cell anergy induction.Key words: Anergy . CD8 1 T cells . NF-kB pathway . Tolerance IntroductionUnderstanding the signals that lead to T-cell tolerance versus activation has the potential to be clinically applicable for treatment of autoimmune diseases and promoting anti-tumor responses. Events associated with the induction of T-cell tolerance versus activation are thought to be determined during T-cell interactions with DC. Recognition of Ag together with costimulatory and proinflammatory signals are believed to elicit optimal T-cell activation.Although recent work has identified several molecules that are involved in influencing the anergic state [1,2], it remains unclear how different molecules are connected and integrated by the T cell to induce tolerance or activation. The serine/threonine Eur. J. Immunol. 2010. 40: 867-877 DOI 10.1002 Leukocyte signaling 867 kinase PKCy lies downstream of the TCR and is involved in the activation of NF-kB, AP-1 and NFAT [3][4][5]. Costimulatory signals through CD28 enhance both the recruitment of PKCy to the immunological synapse and its activation [6][7][8][9][10]. Furthermore, studies from several groups support a central role for PKCy in controlling T-cell activation versus anergy [11][12][13]. To further delineate a molecular pathway that is important for the induction of T-cell anergy versus activation, we wanted to examine the role of molecules downstream of PKCy. PKCy activates NF-kB via the CARMA/Bcl-10/MALT complex [14]. Like PKCy À/À T cells [3,4], the T lymphocytes from mice deficient in any of these three molecules show decreased NF-kB activation and have defects in activation and proliferation. The NF-kB family is composed of five members: c-Rel, RelA, RelB, NF-kB1 (p50/p105) and NF-kB2 (p52/p100). Some functions are unique to specific members of this family; for example, RelA deficiency is embryonic lethal due to apoptosis of fetal hepatocytes [15,16]. Significan...

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CD4+ and CD8+ T Cell Survival Is Regulated Differentially by Protein Kinase Cθ, c-Rel, and Protein Kinase B

Cited by 47 publications

References 70 publications

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Requirement of Calcineurin Aβ for the Survival of Naive T Cells

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance

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CD4+ and CD8+ T Cell Survival Is Regulated Differentially by Protein Kinase Cθ, c-Rel, and Protein Kinase B

Cited by 47 publications

References 70 publications

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Requirement of Calcineurin Aβ for the Survival of Naive T Cells

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8+ T‐cell activation versus tolerance

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c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance