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Investigations into the Cellular Sources of Type 2 Cytokines and Interleukin-17A using Cytokine Reporter Mice

  • Author(s): Price, April
  • Advisor(s): Locksley, Richard M
  • et al.
Abstract

Cytokines play a pivotal role in the maintenance of homeostasis and in the coordination of immune responses. Our lab has designed a variety of cytokine reporter mice, which allow for the determination of cellular sources of cytokines directly in vivo. In this dissertation, reporter mice designed to mark cells expressing IL-4, IL-5, IL-13, IFN-gamma, and IL-17A are described.

First, we focused on type 2 immunity, an immune program that is induced in response to allergens and parasitic helminths. We used IL-4 and IL-13 reporter mice to identify and characterize a subset of lineage-negative cells called Ih2 cells that participate in type 2 immune responses in vivo. We demonstrated that Ih2 cells were widely distributed at rest. We further showed that these cells expanded robustly in response to the epithelial cytokines IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis. Finally, we demonstrated that activation of Ih2 cells with IL-25 is sufficient to mediate worm clearance, even in the absence of adaptive immunity.

Next, we used an IL-17A reporter mouse to identify cells that participate in IL-17-associated immune responses, which are involved in host defense against extracellular bacteria and fungi and also in the development of certain autoimmune disorders. We demonstrated that during Klebsiella pneumoniae infection or experimental autoimmune encephalomyelitis, a substantial proportion of gamma-delta T cells, invariant (i)NKT cells, and other CD4- CD3+ cells and a smaller percentage of CD4+ T cells were marked with the reporter in vivo. Administration of IL-1beta and/or IL-23 elicited rapid expression of the reporter by resident gamma-delta T cells, iNKT cells and other CD4- CD3+ cells in vivo, demonstrating that these innate-like T cells are poised for rapid IL-17A production and likely comprise major sources of this cytokine during infection and autoimmunity.

Taken together, the results of these studies suggest that the cytokines associated with type 2 or IL-17-associated immune responses can be produced by a wide variety of cell types, including innate cells, innate-like T cells, and adaptive immune cells. Coordination of the effector functions of these various cell types is likely critical for the efficacy of these immune programs.

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