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R. Mahdi, C.–R. Yu, H. Takase, K. Song, I. Gery, C.E. Egwuagu; Suppressor of Cytokine Signaling (SOCS) Proteins: Role in T–cell Activation and Homeostatic Regulation of Th1/Th2 Effector Functions . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2821.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Cytokine and TCR (T–cell receptor) play crucial roles in regulating Th1/Th2 differentiation and maintenance of immune homeostasis. Recent studies have revealed that SOCS proteins are important negative regulators of TCR and cytokine signaling. In this study, we have investigated whether SOCS expression is Ag–dose–dependent and if T–cell trafficking or homeostatic regulation of Th1 & Th2 effector functions is sensitive to steady–state levels of SOCS proteins. Methods: CD4+ Th lymphocytes isolated from spleens and lymph nodes of hen egg lysozyme (HEL)–specific TCR transgenic and STAT1–/– mice were stimulated with HEL and antigen presenting cells (APC) or anti–CD3/anti–CD28 antibodies, or under neutral (Thn), Th1 or Th2 polarizing conditions. Immunophenotypic analysis were performed by FACS using labeled anti–CD25, –CD62L, CD44, CD45RB, CD69 Abs and percentage of cells secreting Th1 or Th2 cytokines was assessed by intracellular staining with anti–IFN–γ and –IL–4 Abs. SOCS expression was quantified by real–time PCR. Chemokine receptor (CCR7) gene expression was analyzed by RNAse protection assay and effect of SOCS on CCR7 was examined in Th2 stable transformants over–expressing sense or anti–sense SOCS1/SOCS3 cDNA expression constructs. Results:We show here that prolonged activation of naïve T–cells with low Ag doses induces high levels of SOCS1 and SOCS3, lower levels of cellular activation (CD62Lhigh, CD25low, CD44low), diminished proliferation potential (low IL–2 secretion) and up–regulated expression of Th2 cytokines (IL–5 and IL–10) in a time dependent manner. Enhanced expression of SOCS1 also up–regulates transcription of CCR7 and potentially promotes migration of T cells into lymphoid tissues. On the other hand, STAT1–/– Th cells that have much lower SOCS1 levels, express much higher CD44 activation marker and have lower Ag–activation threshold. Conclusions: Taken together, our results suggest that the level of SOCS expression in T–cells depends on strength of the TCR signal and that the T–cell activation threshold is in turn sensitive to steady–state levels of SOCS proteins. Thus, SOCS proteins play important roles not only in regulating T–helper cell differentiation, but may also influence T–cell homeostasis by influencing T–cell activation threshold and their migration capacity.
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