Regulatory T cells (T(reg) cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T(reg) cell development. Mice that lacked all Nr4a factors could not produce T(reg) cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T(reg) cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis.

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...

Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4+ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction.