Soil transmitted parasitic nematodes are world wide one of the most commonly acquired infections with multicellular parasites. The adaptive host response in humans and mice is characterized by the presence of CD4+ Th2 cells and their signature cytokine IL-4. Th2 cells and IL-4 are associated with protective immune responses against helminth parasites they are detrimental in certain immunopathologies such as antigen-induced asthmatic reactions, atopy and allergy. While Th2 cells are associated with nematode infections;however, it is not clear how Th2 cells develop from naive CD4+ T cells in response to infection/ Numerous studies have shown that IL-4Ra-mediated signals and IL-4 are required for the Th2 development of naive CD4+ T cells in vitro, however, very little is known about these processes in vivo. This is largely due to the difficulty to identify and track Th2 cells defined by IL-4 expression. To overcome these limitations we have developed bicistronic IL-4 reporter (4get) mice. In contrast to in vitro studies, our preliminary data show that Th2 priming occurs surprisingly efficient in IL4Ra-/- 4get mice infected with the murine helminth H. polygyrus. Thus, the role of IL-4R and IL-4 for Th2 development is controversial. Recently we have generated novel IL-4 dual-reporter mice (4get/KN2) and revealed that IL-4 competence and IL-4 production are distinct steps. Here we propose a novel model whereby Th2 development and IL-4 production occur in several distinct, identifiable steps: 1. activation, 2. differentiation, 3. expansion, 4. IL-4 production, 5. dissemination. In the current application we will revisit the role of IL-4 and IL-4Ra-mediated signals for Th2 differentiation and IL-4production using our unique dual-reporter mouse model. We hypothesize that IL-4R functions are not required to nucleate the Th2 priming of CD4+ T cells but play a role in multiple other steps of this model.
In Aim 1 we will analyze which step(s) in Th2 differentiation of the endogenous T cell population are regulated by IL-4R signals in response to infection.
In Aim 2 we will determine which step(s) in Th2 differentiation are regulated by IL-4R signals mediated directly on naive, antigen-specific CD4+ T cells. We will adoptively transfer apTCR transgenic CD4+ T cells and immunize with the cognate antigen using H. polygyrus larvae as a Th2 adjuvant.
In Aim 3 we will dissect the role of IL-4 and IL-4Ra expression by selective lineages in the multi-step process of Th2 differentiation. We will generate various bone marrow chimeras which lack the respective components in selective cellular lineages and follow the development of the endogenous T helper response to infection. Collectively the proposed Aims will reveal the mechanism by which IL-4R and IL-4 regulate the multiple steps of Th2 development in vivo. These insights are valuable for designing agonistic and antagonistic intervention strategies targeting the IL-4R and IL-4.
|King, I L; Mohrs, K; Meli, A P et al. (2017) Intestinal helminth infection impacts the systemic distribution and function of the naive lymphocyte pool. Mucosal Immunol 10:1160-1168|
|Perona-Wright, Georgia; Kohlmeier, Jacob E; Bassity, Elizabeth et al. (2012) Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response. Proc Natl Acad Sci U S A 109:18535-40|
|Perona-Wright, Georgia; Mohrs, Katja; Mayer, Katrin D et al. (2010) Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo. J Immunol 184:615-23|
|Perona-Wright, Georgia; Mohrs, Katja; Mohrs, Markus (2010) Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat Immunol 11:520-6|
|King, Irah L; Mohrs, Katja; Mohrs, Markus (2010) A nonredundant role for IL-21 receptor signaling in plasma cell differentiation and protective type 2 immunity against gastrointestinal helminth infection. J Immunol 185:6138-45|
|King, Irah L; Mohrs, Markus (2009) IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med 206:1001-7|
|Zaretsky, Arielle Glatman; Taylor, Justin J; King, Irah L et al. (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206:991-9|
|Perona-Wright, Georgia; Mohrs, Katja; Szaba, Frank M et al. (2009) Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe 6:503-12|
|Taylor, Justin J; Krawczyk, Connie M; Mohrs, Markus et al. (2009) Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression. J Clin Invest 119:1019-28|
|Perona-Wright, Georgia; Mohrs, Katja; Taylor, Justin et al. (2008) Cutting edge: Helminth infection induces IgE in the absence of mu- or delta-chain expression. J Immunol 181:6697-701|
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