Although it has been well established that TGF-β plays a pivotal role in immune regulation, the roles of its downstream transcription factors, Smad2 and Smad3, have not been fully clarified. Specifically, the function of Smad2 in the immune system has not been investigated because of the embryonic lethality of Smad2-deficient mice. In this study, we generated T cell-specific Smad2 conditional knockout (KO) mice and unexpectedly found that Smad2 and Smad3 were redundantly essential for TGF-β–mediated induction of Foxp3-expressing regulatory T cells and suppression of IFN-γ production in CD4+ T cells. Consistent with these observations, Smad2/Smad3-double KO mice, but not single KO mice, developed fatal inflammatory diseases with higher IFN-γ production and reduced Foxp3 expression in CD4+ T cells at the periphery. Although it has been suggested that Foxp3 induction might underlie TGF-β–mediated immunosuppression, TGF-β still can suppress Th1 cell development in Foxp3-deficient T cells, suggesting that the Smad2/3 pathway inhibits Th1 cell development with Foxp3-independent mechanisms. We also found that Th17 cell development was reduced in Smad-deficient CD4+ T cells because of higher production of Th17-inhibotory cytokines from these T cells. However, TGF-β–mediated induction of RORγt, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-β regulates Th17 development through Smad2/3-dependent and -independent mechanisms.

Abstract-Various cytokines are involved in the regulation of the immune system and inflammation. Dysregulation of cytokine signaling can cause a variety of diseases, including allergy, autoimmune diseases, inflammation, and cancer. Key Words: cytokines Ⅲ immune system Ⅲ leukocytes C ytokines play several essential roles in the development, differentiation, and function of myeloid and lymphoid cells. Some of them, including interleukins (ILs), interferons (IFNs), and hematopoietic growth factors, activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. 1 In this pathway, cytokine binding results in receptor oligomerization, which initiates the activation of JAK kinases (JAK1, JAK2, JAK3, and Tyk2). The activated JAKs phosphorylate the receptor cytoplasmic domains, which creates docking sites for sec-homology-2 (SH2)-containing signaling proteins. Members of the signal transducers and activators of transcription family of proteins (STATs) are major substrates of JAKs. It is now known that a large number of cytokines, growth factors, and hormonal factors also activate JAK and STAT proteins; for example, proinflammatory cytokine IL-6 binds to the IL-6 receptor ␣ chain and to gp130, both of which mainly activate JAK1 and STAT3. IFN␥ receptors use JAK1 and JAK2, although it mainly activates STAT1. Interestingly, antiinflammatory cytokine IL-10 also activates STAT3. For helper T (Th) cell development, IL-6/IL-23, IL-12, and IL-4 activate STAT3, STAT4, and STAT6 respectively ( Figure 1B). STAT3, STAT1/4, and STAT6 are essential for Th17, Th1, and Th2 differentiation, respectively. 2 STAT5 is essential for regulatory T cell (Treg) development. 2 The action of STAT5 also appears to be very direct, as STAT5 binds the Foxp3 gene, the master regulator of Tregs (see Figure 2).Although our understanding of the intracellular signaling molecules that mediate the functional outcome of cytokinereceptor activation has increased profoundly, the most recent research has placed increasing emphasis on the mechanisms for the termination of signals and cross-talks with other signaling pathways. The cytokine-inducible SH2-containing (CIS)/suppressors of cytokine signaling (SOCS) family proteins are a major mechanism for such regulation. [3][4][5] At the time of their discovery, the SOCS proteins were recognized as an important mechanism for the negative regulation of the cytokine-JAK-STAT pathway, but recent studies using genedisrupted mice have revealed that they play additional, unexpected, and profound roles in many immunologic processes. 4,5 Because space is limited, we will focus on the recent progress of SOCS1 and SOCS3 studies on inflammation and Th cell differentiation. The CIS/SOCS FamilySuppressor of cytokine signaling (SOCS) proteins and CIS (also known as CISH) protein molecules make up a family of intracellular proteins. [3][4][5] There are 8 CIS/SOCS family proteins: CIS, SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, and SOCS7, each of which has a central SH2 domain, an amino-terminal do...

SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells.