Date of Award

Fall 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

David Artis

Abstract

CD4+ T helper (Th) 2 cells secrete interleukin (IL)-4, IL-5 and IL-13 and promote immunity to gastrointestinal helminth infections and chronic inflammation associated with asthma and allergic disorders. However, the innate immune pathways that promote Th2 cell responses remain poorly characterized. The non-hematopoietic cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 (IL-17E) have been implicated in promoting Th2 cell-dependent inflammation at mucosal sites [1-4], but how these cytokines influence innate immune responses are less well defined. Studies in Chapter 2 and 3 examined the cellular mechanisms through which IL-25 promotes Th2 cell responses and demonstrated that IL-25 promotes the accumulation of a previously unrecognized non-B/non-T cell (NBNT) c-kit+ cell population in the gut-associated lymphoid tissue (GALT). Adoptive transfer of IL-25-elicited c-kit+ cells promoted Th2 cytokine responses and conferred protective immunity to helminth infection in normally susceptible Il17e-/- mice. In Chapter 3, characterization of the IL-25-elicited c-kit+ cells revealed these cells to be a lineage negative (Linneg) multi-potent progenitor (MPP) cell population. This cell population, termed MPPtype2 cells, exhibited multi-potent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. These data indicate the IL-25-elicited MPPtype2 cells may contribute to extramedullary hematopoiesis in vivo. The relationships between MPPtype2 cells and other recently identified innate cell populations, including natural helper cells (NHCs), nuocytes, and innate type 2 helper (Ih2) cells were examined in Chapter 4. MPPtype2 cells were found to be phenotypically distinct from nuocytes, NHCs and Ih2 cells. Further, stimulation of IL-25-elicited MPPtype2 cells with TSLP and IL-33 resulted in the differentiation of these cells into a T1/ST2+ IL7Rα+ NHC/nuocyte-like cell population, indicating that MPPtype2 cells could be progenitors of NHC/nuocytes. Combined, the results presented in this thesis demonstrate that IL-25 induces the emergence of a previously unrecognized multi-potent progenitor cell population and suggests that extramedullary hematopoiesis is an evolutionary conserved pathway that promotes Th2 cytokine responses at mucosal sites.

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