Recently, a third subset of TH cells, named as TH IL-17 , TH17, or inflammatory TH (THi), which produce IL-17, was identified by us as well as other investigators to mediate a pathogenic inflammatory response (5-7). THi cells were also found to produce IL-17F and IL-22 (5, 7-9). IL-23, sharing a p40 unit with IL-12, has been first found to regulate IL-17 expression and the development or expansion of THi cells in vitro (5-7). More recently, several groups showed that TGF-␤ in the context of IL-6 and other inflammatory cytokines supports THi differentiation in vitro, independent of IL-23 (10 -12), possibly at least in part by regulating the chromatin remodeling of the IL-17-IL-17F locus (13). IL-1␤ and TNF-␣ may also be involved in promoting THi development or in regulating expression of IL-17 at the effector phase (11,14).The downstream signaling pathways, such as STAT, that selectively mediate THi generation are unclear. STAT1 appears to negatively regulate THi differentiation (7), whereas STAT4 or STAT6 were not involved (6). Recently, Socs3-deficient T cells were found to exhibit enhanced IL-17 expression; this effect was associated with enhanced activity of STAT3 in response to IL-23 that could bind to . STAT3 has critical functions in the immune system, including control of dendritic cell production, inhibition of macrophage inflammatory signaling, and regulation of steady state and emergency granulopoiesis (16 -18). However, the precise physiological function of STAT3 in THi lineage differentiation has not been directly addressed. Whether STAT5, another STAT protein that has been shown activated by , has any function in THi differentiation is also unclear.In this study, we show that IL-6 up-regulates expression of IL-23R and that IL-23 synergizes with IL-6 in promoting THi differentiation. Retroviral expression of a hyperactive STAT3 enhances THi cell development. STAT3 deficiency in CD4 T cells results in impaired THi development and a deficiency in ROR␥t, a THi-specific transcription factor recently identified (20). These data indicate that STAT3 is a cytokine-activated essential regulator in THi development.

A variety of cytokines mediate the activation of Janus protein tyrosine kinases (Jaks). The Jaks then phosphorylate cellular substrates, including members of the signal transducers and activators of transcription (Stat) family of transcription factors. Among the Stats, the two highly related proteins, Stat5a and Stat5b, are activated by a variety of cytokines. To assess the role of the Stat5 proteins, mutant mice were derived that have the genes deleted individually or together. The phenotypes of the mice demonstrate an essential, and often redundant, role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin. Conversely, the responses to a variety of cytokines that activate the Stat5 proteins, including erythropoietin, are largely unaffected.

A variety of cytokines activate receptor-associated members of the Janus family of protein tyrosine kinases (Jaks). To assess the role of Jak2, we have derived Jak2-deficient mice. The mutation causes an embryonic lethality due to the absence of definitive erythropoiesis. Fetal liver myeloid progenitors, although present based on the expression of lineage specific markers, fail to respond to erythropoietin, thrombopoietin, interleukin-3 (IL-3), or granulocyte/macrophage colony-stimulating factor. In contrast, the response to granulocyte specific colony-stimulating factor is unaffected. Jak2-deficient fibroblasts failed to respond to interferon gamma (IFNgamma), although the responses to IFNalpha/beta and IL-6 were unaffected. Lastly, reconstitution experiments demonstrate that Jak2 is not required for the generation of lymphoid progenitors, their amplification, or functional differentiation. Therefore, Jak2 plays a critical, nonredundant role in the function of a specific group of cytokines receptors.

BACKGROUND The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS We observed a significant association (P<1.00×10 −10) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P = 5.10×10 −5) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

Many receptors activate phospholipase Cgamma1 or -gamma2. To assess the role of PLCgamma2, we derived enzyme-deficient mice. The mice are viable but have decreased mature B cells, a block in pro-B cell differentiation, and B1 B cell deficiency. IgM receptor-induced Ca2+ flux and proliferation to B cell mitogens are absent. IgM, IgG2a, and IgG3 levels are reduced, and T cell-independent antibody production is absent. The similarity to Btk- or Blnk-deficient mice demonstrates that PLCgamma2 is downstream in Btk/Blnk signaling. FcRgamma signaling is also defective, resulting in a loss of collagen-induced platelet aggregation, mast cell FcepsilonR function, and NK cell FcgammaRIII and 2B4 function. The results define a signal transduction pathway broadly utilized by immunoglobulin superfamily receptors.