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Browsing by Author "Awe, Olufolakemi"
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Item Diverse inflammatory cytokines induce selectin ligand expression on murine CD4 T cells via p38α MAPK(The American Association of Immunologists, 2015-06-15) Ebel, Mark E.; Awe, Olufolakemi; Kaplan, Mark H.; Kansas, Geoffrey S.; Department of Pediatrics, IU School of MedicineSelectins are glycan-binding adhesion molecules that mediate the initial steps of leukocyte recognition of endothelium. Cytokines control numerous aspects of CD4 Th cell differentiation, but how cytokines control the induction of ligands for E- and P-selectin on Th cell subsets remains poorly understood. Among 20 cytokines that affect Th cell differentiation, we identified six that induce expression of selectin ligands on murine CD4 T cells above the low levels associated with TCR engagement: IL-12, IL-18, IL-27, IL-9, IL-25, and TGF-β1. Collectively, these six cytokines could potentially account for selectin ligand expression on all of the currently defined nonsessile Th cell lineages, including Th1, Th2, Th9, and Th17 cells, as well as regulatory T cells. Induction of selectin ligand expression by each of these six cytokines was almost completely inhibited by pharmacologic inhibition of p38 MAPK, but not other MAPKs, or by conditional genetic deletion of p38α MAPK. Analysis of the expression of key glycosyltransferase genes revealed that p38α signaling was selectively required for induction of Fut7 and Gcnt1 but not for the induction of St3gal4 or St3gal6. Constitutively active MKK6, an immediate upstream activator of p38 MAPK, induced selectin ligand expression equivalent to that of cytokines, and this induction was completely dependent on the expression of p38α. Our results identify the repertoire of cytokines responsible for selectin ligand induction on CD4 T cells and provide a mechanistic link between Th cell development and T cell migration.Item PU.1 expression in T follicular helper cells limits CD40L-dependent germinal center B cell development.(American Association of Immunologists, 2015-10-15) Awe, Olufolakemi; Hufford, Matthew M.; Wu, Hao; Pham, Duy; Chang, Hua-Chen; Jabeen, Rukhsana; Dent, Alexander L.; Kaplan, Mark H.; Department of Microbiology and Immunology, IU School of MedicinePU.1 is an ETS family transcription factor important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development, and in limiting Th2 cytokine production. Whether PU.1 has functions in other T helper lineages is not clear. In this report we examined the effects of ectopic expression of PU.1 in CD4+T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1lck−/−) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck−/− mice had increased numbers of Tfh cells, increased germinal center B cells, and increased antibody production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck−/− mice, compared to control mice. Finally, although blockade of IL-21 did not affect germinal center B cells in Sfpi1lck−/− mice, anti-CD40L treatment of immunized Sfpi1lck−/− mice decreased germinal center B cell numbers and antigen-specific immunoglobulin concentrations. Together, these data indicate an inhibitory role of PU.1 in the function of T follicular helper cells, germinal centers, and Tfh-dependent humoral immunity.Item Th17 cells demonstrate stable cytokine production in a proallergic environment(The American Association of Immunologists, 2014-09-15) Glosson-Byers, Nicole L.; Sehra, Sarita; Stritesky, Gretta L.; Yu, Qing; Awe, Olufolakemi; Pham, Duy; Bruns, Heather A.; Kaplan, Mark H.; Department of Pediatrics, IU School of MedicineTh17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and allergic inflammation. After exposure to an appropriate cytokine environment, Th17 cells can acquire a Th1-like phenotype, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we used an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F. In vitro-derived Th17 cells adopted signature cytokine and transcription factor expression when cultured under Th1-, Th2-, or Th9-polarizing conditions. In contrast, using two models of allergic airway disease, Th17 cells from the lungs of diseased mice did not adopt Th1, Th2, or Th9 effector programs, but remained stable IL-17 secretors. Although in vitro-derived Th17 cells expressed IL-4Rα, those induced in vivo during allergic airway disease did not, possibly rendering them unresponsive to IL-4-induced signals. However, in vitro-derived, Ag-specific Th17 cells transferred in vivo to OVA and aluminum hydroxide-sensitized mice also maintained IL-17 secretion and did not produce alternative cytokines upon subsequent OVA challenge. Thus, although Th17 cells can adopt new phenotypes in response to some inflammatory environments, our data suggest that in allergic inflammation, Th17 cells are comparatively stable and retain the potential to produce IL-17. This might reflect a cytokine environment that promotes Th17 stability, and allow a broader immune response at tissue barriers that are susceptible to allergic inflammation.