Maintenance of immune homeostasis is critical in preventing the development of allergic and autoimmune diseases. The inherent ability of the immune system to alter relative amounts of Th1 and Th2 cell types during the course of an ongoing inflammatory response to a pathogen or antigenic stimuli is an essential aspect of mechanisms that underlie immune homeostatic regulation. An area of significant interest in immunology is to understand mechanisms that instruct host immune system to alter the balance of Th1 and Th2 cells and permit rapid dynamic changes in T-helper cell repertoire in situations where host immunity requires robust Th1 or Th2 responses. Cytokines secreted by Th1 and Th2 cells have been shown to play crucial roles in regulating T-cell activation, differentiation and maintenance of immune homeostasis. Stringent regulation of the intensity and duration of these cytokine signals ensures adequate immunological responses while preventing development of allergic and autoimmune diseases. SOCS (suppressors of cytokine signaling) proteins negatively regulate Th1/Th2 polarizing signals (JI 173: 737) and activation of naive CD4+ T cells (JBC 279: 32592). Whereas SOCS3 is preferentially expressed in Th2 cells, SOCS1 is highly expressed in Th1 cells (JI 168: 3181). In addition, T cell activation transiently down-regulates SOCS3 and its cellular concentration is inversely correlated with IL-2 secretion level. Over-expression of SOCS1 or SOCS3 inhibits TCR-mediated proliferation and activation of STAT6 signaling, suggesting that SOCS proteins are important regulators of T-cell growth and functions. In this study, we investigated whether SOCS expression is regulated by TCR and/or cytokine signals and if SOCS proteins play a role in T-cell homeostasis. We show here that prolonged activation of naive T-cells with low Ag doses induces high levels of SOCS1 and SOCS3 expression, 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. Compared to wild type cells, STAT1-/- Th cells have much lower SOCS1 levels, express much higher CD44 activation marker and have lower Ag-activation threshold. Taken together, our results suggest that SOCS play important roles in regulating T-cell homeostasis by modulating their activation and migration capacity.
