Interleukin-4 is a prototypic immunoregulatory cytokine. It is the central regulator of allergic inflammatory responses, controlling the polarization of naive CD4 T cells to the Th2 phenotype and Ig class switching to IgE. We have previously shown that naive CD4 T cells respond to T cell receptor (TCR) mediated weak signals by activating IL-4 transcription. This early TCR-dependent IL-4 production constitutes the induction phase of Th2 differentiation, followed by an IL-4-dependent polarization phase that completes Th2 differentiation. Both GATA3 and STAT5 were shown to be critical for this TCR-mediated early IL-4 transcription. It has now been demonstrated that such early TCR-dependent IL-4 production also critically requires two E proteins, HEB and E2a, which form a heterodimeric transcription factor. The reliance on weak TCR-mediated stimulation has been demonstrated to be due to T cell receptor-mediated activation of the ERK signaling pathway that blocks Th2 differentiation by preventing transcription of GATA3 and desensitizing the IL-2 receptor preventing activation of STAT5. Strong TCR-mediated signals stimulate ERK phosphorylation, thereby preventing TH2 differentiation and accounting for poor Th2 differentiation at high antigen concentration. Low concentrations of antigen, which activate ERK only weakly, are permissive for early IL-4 production and TH2 differentiation. The targets of ERK action that mediate suppression of GATA3 transcription are under active study as are the transcription factors that mediate TCR induced GATA3 transcription. Over the past few years, the group has turned its attention to the study of innate lymphoid cells (ILCs) that produce type II cytokines. They have shown the existence of a previously poorly appreciated cell population, inflammatory ILC2 (iILC2) cells that only appear in measureable numbers after the natural or artificial induction of IL-25. iILC2 cells express IL-25 receptors but not IL-33 receptors. However, both in vivo and in vitro, after the initial massive expansion in response to IL-25, these cells lose the expression of the IL-25 receptor and express IL-33 receptors, thereafter behaving similarly to conventional ILC2 cells, particularly in response to helminth infection. Indeed, these cells play a major role in protection against N. brasiliensis infection. However, under different conditions of infection or to different inductive conditions, they can develop into ILC3-like cells and provide partial protection to Candida albicans infection. The iILC2 cells appear to be a unique cell population that provides a massive response/differentiation in cases of appropriate stimulation. Our most recent work shows that inflammatory ILC2 cells are not generated in situ; they are circulating cells and are well exchanged in parabiotic mice. By contrast, natural ILC2 cells are tissue-resident cells and they barely exchange in parabiotic mice. Thus, inflammatory ILC2 cells are a unique circulating ILC population that only appears under inflammatory circumstances; they are distinguished from tissue-resident ILCs that are largely self-maintained locally. Surprisingly, intestinal ILC2 cells can give rise to inflammatory ILC2 cells, acting as the immediate precursors to those cells. Intestinal ILC2 cells respond to IL-25 or N. brasiliensis, proliferate, move into lymphatic vessels in an S1P-depndent manner, and then enter blood circulation. Once the cells are in the blood circulation, they migrate to lung, liver, mesenteric lymph nodes, spleen and other sites. Drug interference with this migration interferes with host defense in the lung during helminth infection. As an extension of work on allergic lung disease / asthma, the group found that intranasal Th17 immune response using LPS adjuvant is regulated by IL-1 and IL-6 produced by small macrophages and by alveolar dendritic cell IL-23, favoring Th17 responses. Furthermore, we showed that exogenous IL-1 drastically alters Th1 responses driven by influenza and LCMV infection models and induce IL-17 production. Thus, lung immune responses to potential threats are orchestrated by the cytokine microenvironment but can be repolarized and potentially targeted therapeutically by altering the cytokine milieu. These studies also revealed that when IL-1 is present, inflammatory Th2 cells express IL-1R and produce large amounts of IL-13 and IL-5 but lower amounts of IL-4. Furthermore this leads to exacerbation of allergic responses to house dust mites (HDM) critical in driving asthmatic lung immunopathology, suggesting IL-1 signaling in CD4 T cells may be a critical target in allergic asthma. A lymphocyte related to TH2 cells called a T follicular helper (Tfh) plays an important role in humoral immunity. E-box binding proteins (E-proteins) regulate cell differentiation, but the underlying mechanisms remain elusive. We found that CD4+ T cells lacking E-protein activity failed to down-regulate EBI2, a chemoattractant receptor for 7,25-dihydroxycholesterol secreted by stromal cells in outer T cell zone of the spleen. Sustained EBI2 expression kept these Tfh in the outer T cell zone. They failed to migrate to B cell follicles and become germinal center (GC) Tfh cells, despite normal expression of Tfh-related genes. The impaired Tfh differentiation was accounted for by aberrant Eomes expression, since combined loss of Eomes with E-proteins caused EBI2 down-regulation and restored GC Tfh differentiation. Our results indicate that E-proteins play a critical role in down-regulating EBI2 expression on antigen-primed CD4+ T cells by suppressing Eomes, thus promoting CXCL13/CXCR5-dependent migration to B cell follicles and subsequent maturation into GC Tfh cells.
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| Kummola, Laura; Ortutay, Zsuzsanna; Chen, Xi et al. (2017) IL-7R? Expression Regulates Murine Dendritic Cell Sensitivity to Thymic Stromal Lymphopoietin. J Immunol 198:3909-3918 |
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| Huang, Yuefeng; Guo, Liying; Qiu, Jin et al. (2015) IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential 'inflammatory' type 2 innate lymphoid cells. Nat Immunol 16:161-9 |
| Paul, William; Neill, Ushma S (2015) A conversation with Bill Paul. J Clin Invest 125:1367-8 |
| Helmstetter, Caroline; Flossdorf, Michael; Peine, Michael et al. (2015) Individual T helper cells have a quantitative cytokine memory. Immunity 42:108-22 |
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| Dewas, Cedric; Chen, Xi; Honda, Tetsuya et al. (2015) TSLP expression: analysis with a ZsGreen TSLP reporter mouse. J Immunol 194:1372-80 |
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