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YongJun Lee, Charles E. Egwuagu; Signal Transducer And Activator Of Transcription 3 (stat3) Regulates Cd8+ T Cell Cell-fate Decisions And Effector Functions. Invest. Ophthalmol. Vis. Sci. 2011;52(14):527.
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Signal transducer and activator of transcription 3 (STAT3) is an important signaling pathway implicated in regulating proliferation and differentiation of CD4+ Th17 subset. However, the role of STAT3 in CD8+ T cells is not well understood. The goal of this study was to investigate if STAT3 regulates CD8+ T cell developmental program and effector functions.
We generated mice with conditional deletion of STAT3 in CD8+ T cells by breeding STAT3fl/fl mice with mice with targeted expression of Cre protein in T cells. Sorted naïve CD62L+CD44loCD8+ T cells were stimulated with anti-CD3/CD28 under Tc0, Tc1 condition in vitro. The level of interleukin-2 (IL-2), gamma-interferon (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were assayed by intracellular cytokine staining. Expression of apoptosis-related genes was analyzed by RT-PCR, real-time PCR and flow cytometry. Apoptotic cells were determined by staining with annexin-V and flow cytometry. CD8+ T cells were labeled with CFSE, stimulated under Tc0 or Tc1 condition and the role of STAT3 in CD8+ T cell proliferation was assessed by CFSE dilution.
We found that STAT3-deficient CD8+ T cells produced less IL-2, IFN-γ, and TNF-α compared to WT T cells cultured under Tc0 or Tc1 condition. We further show that STAT3-deficient T cells exhibited significantly higher proliferative capacity as indicated by CFSE dilution assay and they were more susceptible to activation induced cell death as revealed by annexin-V staining assay. In addition, the increase in apoptosis correlated with enhanced expression of genes coding for pro-apoptotic proteins (e.g. Bax, caspase 8, FasL).
Our data suggest that STAT3 regulates CD8+ T cell proliferation, effector functions and protects CD8+ T cells from activation induced cell death. Further studies using these mice with conditional deletion of STAT3 in CD8+ T cells will undoubtedly be valuable in understanding the role of this enigmatic transcription factor in the differentiation and development of CD8+ T cells.
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