Soil transmitted parasitic nematodes are world wide one of the most commonly acquired infections with multi-cellular 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-4 production 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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI072296-01
Application #
7184468
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Quill, Helen R
Project Start
2006-11-15
Project End
2011-10-31
Budget Start
2006-11-15
Budget End
2007-10-31
Support Year
1
Fiscal Year
2007
Total Cost
$399,375
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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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