Nicotine Activates Nuclear Factor of Activated T Cells c2 (NFATc2) and Prevents Cell Cycle Entry in T Cells

Frazer‐Abel, Ashley; Baksh, Shairaz; Fosmire, Susan; Willis, Derall G.; Pierce, Angela; Meylemans, Heather; Linthicum, D. Scott; Burakoff, Steven J.; Coons, Teresa; Bellgrau, Donald; Modiano, Jaime F.

doi:10.1124/jpet.104.070060

Cited by 26 publications

(32 citation statements)

References 40 publications

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“…The functional significance of this finding was confirmed in the Nfatc2-deficient mice that had enhanced CDK4 expression and activity restricted to the peripheral T cell pool, which shows dysregulated expansion in these animals (43,44). An important finding from this work was that the association of Nfatc2 with AP-1 transcription factors was a critical determinant of its activity as a transcriptional activator or a transcriptional repressor.…”

Section: Nfatc2 In Negative Regulation and Survivalmentioning

confidence: 77%

“…It is now apparent that survival and quiescence are actively enforced in T cells (41)(42)(43)(44)(45)(46)(47). This paradigm has long been operative in other systems where survival requires signals from a substrate or matrix (avoidance of anoikis) (48,49) and where quiescence is enforced by signals delivered when cells contact each other (50).…”

Section: Intrinsic Negative Regulators Of T Cell Activationmentioning

confidence: 99%

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Negative regulators in homeostasis of naïve peripheral T cells

2008

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It is now apparent that naïve peripheral T cells are a dynamic population where active processes prevent inappropriate activation while supporting survival. The process of thymic education makes naïve peripheral T cells dependent on interactions with self-MHC for survival. However, as these signals can potentially result in inappropriate activation, various non-redundant, intrinsic negative regulatory molecules including Tob, Nfatc2, and Smad3 actively enforce T cell quiescence. Interactions among these pathways are only now coming to light and may include positive or negative crosstalk. In the case of positive crosstalk, self-MHC initiated signals and intrinsic negative regulatory factors may cooperate to dampen T cell activation and sustain peripheral tolerance in a binary fashion (on-off). In the case of negative crosstalk, self-MHC signals may promote survival through partial activation while intrinsic negative regulatory factors act as rheostats to restrain cell cycle entry and prevent T cells from crossing a threshold that would break tolerance. KeywordsT cells; MHC; sensitization; desensitization; cell cycle; negative regulation; tolerance The Influence of Self-MHC in T-Cell Quiescence and Survival Self-MHC and naïve T cell survivalThe role of self-peptides complexed to major histocompatibility complex proteins (self-MHC) to maintain homeostasis of naïve T cells has been the subject of extensive investigation over the past decade. This work has revealed apparent differences in the sensitivity of different T cell subsets to the absence of self-MHC. Perhaps the most informative experiments have attempted to characterize the expansion of peripheral lymphocytes in MHC-replete or MHCdeficient lymphopenic environments. The idea that "space" in the peripheral lymphoid organs drove lymphocyte proliferation arose from the observation that under conditions of lymphopenia such as those produced by non-myeloablative, lymphodepleting regimens in humans or mice, or under conditions encountered by adoptively transferred lymphocytes or bone marrow cells into lymphopenic hosts, T cells would expand without exogenous antigens. It is now apparent that this "lymphopenia-induced proliferation" or "homeostatic proliferation" (HP) results not only from "space", but also from interactions of T cell receptors (TCR) with self-MHC, and from lessened competition for cytokines including interleukin-7 (IL-7), or in some cases, Unlike HP in MHC-replete hosts, a majority of naïve T cells die or make at most a few divisions if the lymphopenic periphery is devoid of MHC (16-21), a result consistent with the premise that HP is itself partly driven by recognition of self-MHC complexes. Both CD4 and CD8 T cells undergo HP, although CD4 T cells expand less in response to MHC and CD8 T cells are more sensitive to its absence. In fact, while the requirement for self-MHC in naïve CD8 T cell survival is generally accepted (although it may not apply to all CD8 T cell subsets) (22), the delayed erosion of naïve CD4 T cells in lymphopenic h...

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Section: Nfatc2 In Negative Regulation and Survivalmentioning

confidence: 77%

Section: Intrinsic Negative Regulators Of T Cell Activationmentioning

confidence: 99%

Negative regulators in homeostasis of naïve peripheral T cells

2008

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“…Among >160 genes in HSA 7p, diacylglycerol kinase-h and histone deacetylase-9 are two potentially ''novel'' tumor suppressor genes (43,44). In the context of chromosome gains seen in canine T-cell lymphomas, candidates that may encode ''novel'' oncogenes include interleukin-15, FK506 binding protein-7, and histone acetyltransferase-1, which map to HSA 4q31, 2q31.3, and 2q31.2-33.1, respectively, and could initiate autocrine growth loops (45,46), lower total calcineurin and NFATc2 activity (47), or counteract the activity of histone deacetylase (48).…”

Section: Discussionmentioning

confidence: 99%

Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk

et al. 2005

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Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor ; chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using C 2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD. (Cancer Res 2005; 65(13): 5654-61)

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“…Interestingly, it is documented that chronic exposure to cigarette compounds such as nicotine suppresses immune functions including T-cell proliferation. 33,34 A study by Frazer-Abel et al 15 showed that direct addition of nicotine to T cells in vitro decreases their proliferation by prevention of cell-cycle entry in G 0 -G 1 transition. However, the present results imply that smoking exerts differential effects in patients leading to altered T-cell proliferation and that these effects are disease associated rather than related to smoking as no proliferative difference was observed between healthy smokers and non-smokers.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Nicotine, the major active chemical in cigarettes, has been shown to impair antigen-driven T-cell response and inhibit proliferation in rodents as well as humans. [13][14][15][16] T lymphocytes have integral function in cell-mediated immunity and are involved in host defence against infectious agents. Peripheral changes in the immune system of schizophrenia patients, such as decreased cellular immune response 17,18 and altered cytokineexpression, 19 have been reported.…”

Section: Introductionmentioning

confidence: 99%

Differential effects on T-cell function following exposure to serum from schizophrenia smokers

et al. 2008

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Cigarette smoking is more prevalent in subjects with schizophrenia compared to those with other psychiatric disorders or the general population and could therefore affect molecular pathways that impact the pathophysiology of this disorder. As smoking is also known to suppress immune responses, we investigated the effects of 'smoking-conditioned' serum obtained from schizophrenia and control subjects on healthy T cell in vitro. We found that T-cell proliferation was significantly increased following exposure to serum from smoking schizophrenia patients whereas no effect was observed when using serum from smoking control subjects or non-smoking patients and controls. We eliminated the possibility that these effects were due to quantitative differences in cigarette consumption as serum levels of the stable nicotine metabolite cotinine were similar in schizophrenic and control smokers. Molecular characterization showed that serum from patient smokers increased expression of T-cell activation markers CD69 high , CD25 high , co-stimulatory molecules CD26 þ , CD27 þ and CD28 þ , and decreased T-cell receptor complex components TCRa/b and CD3. Moreover, analysis of supernatants collected after T-cell exposure to serum from smoking patients showed a time-dependent decline in interleukin (IL)-2 levels, suggesting that the proliferation effect is promoted by enhanced IL-2 processing. These results suggest that cigarette smoking has selective effects on serum components that, in turn, lead to altered immune function in schizophrenia patients relative to healthy subjects. Further studies aimed at characterizing these components could result in a better understanding of the onset and aetiology of schizophrenia and potentially lead to novel therapeutic strategies.

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Nicotine Activates Nuclear Factor of Activated T Cells c2 (NFATc2) and Prevents Cell Cycle Entry in T Cells

Cited by 26 publications

References 40 publications

Negative regulators in homeostasis of naïve peripheral T cells

Negative regulators in homeostasis of naïve peripheral T cells

Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk

Differential effects on T-cell function following exposure to serum from schizophrenia smokers

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