In vivo studies fail to reveal a role for IL4 or STAT6 signaling in Th2 lymphocyte differentiation (original) (raw)
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Infection and Immunity, 2008
The role of CD4 ؉ T-cell interleukin-4 (IL-4) receptor alpha (IL-4R␣) expression in T helper 2 (TH2) immune responses has not been defined. To examine this role, we infected CD4 ؉ T-cell IL-4R␣ knockout (KO) mice with the parasitic nematode Nippostrongylus brasiliensis, which induces strong host TH2 responses. Although N. brasiliensis expulsion was not affected in CD4 ؉ T-cell IL-4R␣ KO mice, the associated lung pathology was reduced. Infected CD4 ؉ T-cell IL-4R␣ KO mice showed abrogation of airway mucus production. Furthermore, CD4 ؉ T-cell IL-4R␣ KO mouse lungs contained reduced numbers of lymphocytes and eosinophils. Restimulation of pulmonary region-associated T-cell populations showed that TH2 cytokine responses were disrupted. Secretion of IL-4, but not secretion of IL-13 or IL-5, from mediastinal lymph node CD4 ؉ T cells was reduced in infected CD4 ؉ T-cell IL-4R␣ KO mice. Restimulation of tissue-derived CD4 ؉ T cells resulted in equivalent levels of IL-4 and IL-13 on day 7 postinfection (p.i.) in control and CD4 ؉ T-cell IL-4R␣ KO mice. By day 10 p.i. the TH2 cytokine levels had significantly declined in CD4 ؉ T-cell IL-4R␣ KO mice. Restimulation with N. brasiliensis antigen of total lung cell populations and populations with CD4 ؉ T cells depleted showed that CD4 ؉ T cells were a key TH2 cytokine source. These data demonstrated that CD4 ؉ T-cell IL-4 responsiveness facilitates eosinophil and lymphocyte recruitment, lymphocyte localization, and TH2 cytokine production in the allergic pathology associated with N. brasiliensis infections.
Allergen-induced Th2-independent production of IL-4 in the airways of mice
Matters (Zürich), 2016
It is thought that release of cytokines from allergen-damaged epithelial cells induces production of an innate source of IL-4 and IL-13 that are important in initiating adaptive T-helper type II (Th2)-mediated allergic responses. However, detecting innate production of IL-4 or IL-13 in vivo is difficult due to high levels of adaptive production of IL-4 and IL-13 by Th2 cells. The IL-4 receptor (IL-4R) and the IL-4/13 co-receptor (IL-13R) share a common receptor subunit (IL-4Ra). Consequently, both IL-4 and IL-13 signal via the IL-4Ra-associated signaling molecule, signal transducer and activator of transcription factor 6 (STAT6). STAT6 signaling in T-cells, B-cells, and airway epithelial cells is essential for Th2 differentiation, isotype class switching to IgE, and mucus production, respectively. Therefore, Epi-STAT6 mice (STAT6-/-mice with airway epithelial-specific transgenic STAT6 expression) are defective in Th2 immune responses but can produce mucus in response to IL-4 and/or IL-13 in their airways. As compared to wildtype mice, allergen-challenged Epi-STAT6 mice were deficient in IgE production and the levels of IL-13 expressed were not above appropriate controls. However, significant levels of IL-4 and mucin gene expression were detected in their lungs. These observations support the existence of an allergen-responsive, non-Th2-derived source of IL-4 in the airways of mice.
Allergy, 2000
Background: Interleukin (IL)-4 is believed to play an important role in the atopic pathogenesis. However, the precise role of IL-4 in the in vivo initiation of allergic rhinitis is not fully understood. We have recently found that BALB/c mice sensitized intranasally with Schistosoma mansoni egg antigen (SEA) mount a Th2 response that initiates allergic rhinitis. Thus, we sought to determine the role of IL-4 in the initiation of allergic rhinitis in vivo with this model. Methods: IL-4 gene-de®cient (IL-4x/x) BALB/c and wild-type (IL-4+/+) control mice were sensitized by intranasal SEA administration, and their immunologic responses were examined both in vivo and in vitro. Results: IL-4+/+ mice sensitized with SEA displayed signi®cantly higher titers of SEA-speci®c IgG1 and IgE antibodies than IL-4x/x mice, while the latter produced signi®cantly more SEA-speci®c IgG2a. Antigen-stimulated nasal lymphocytes from SEA-sensitized IL-4x/x and IL-4+/+ mice produced similar amounts of IL-5 and IL-10, but neither produced IFN-c. Furthermore, the severity of nasal eosinophilia was similar in both groups. Conclusions: These results indicate that although IL-4 is necessary for the production of Th2-associated antibodies ± in particular, IgE ± it is not required for either the production of the Th2-associated cytokines IL-5 and IL-10, or the induction of nasal eosinophilia.
The Journal of Immunology, 2005
The intestinal nematode parasite, Nippostrongylus brasiliensis, triggers potent type 2 immunity. Using OVA peptide as a model Ag, we have examined the adjuvant effects of this parasite on the in vivo development of Ag-specific Th2 cells from naive DO11.10 T cells. Our findings show that Th2 cells can develop from transferred naive OVA-specific DO11.10 T cells in recipient IL-4−/− mice inoculated with N. brasiliensis plus OVA. However, autocrine IL-4 is required for in situ Th2 cell differentiation since transferred IL-4Rα-deficient DO11.10 T cells showed greatly reduced Th2 cell development in inoculated IL-4−/− recipient mice. Surprisingly, we also found that IL-2 blockade promoted B7-dependent T cell cycling, but inhibited the development of OVA-specific Th2 cells. Furthermore, the effects of IL-2 occurred independently of CD25+ T regulatory cells. These studies establish a previously unrecognized requirement for autocrine IL-4 and IL-2 in Th2 responses elicited by nematode parasi...
Lack of IL-12 signaling in human allergen-specific Th2 cells
Journal of immunology (Baltimore, Md. : 1950), 1996
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-...
Basophils Produce IL4 and Accumulate in Tissues after Infection with a Th2-inducing Parasite
Using mice in which the eGfp gene replaced the first exon of the Il4 gene (G4 mice), we examined production of interleukin (IL)-4 during infection by the intestinal nematode Nippostrongylus brasiliensis (Nb). Nb infection induced green fluorescent protein (GFP) pos cells that were Fc RI pos , CD49b bright , c-kit neg , and Gr1 neg . These cells had lobulated nuclei and granules characteristic of basophils. They were found mainly in the liver and lung, to a lesser degree in the spleen, but not in the lymph nodes. Although some liver basophils from naive mice express GFP, Nb infection enhanced GFP expression and increased the number of tissue basophils. Similar basophil GFP expression was found in infected Stat6 ϪրϪ mice. Basophils did not increase in number in infected Rag2 ϪրϪ mice; Rag2 ϪրϪ mice reconstituted with CD4 T cells allowed significant basophil accumulation, indicating that CD4 T cells can direct both tissue migration of basophils and enhanced IL-4 production. IL-4 production was immunoglobulin independent and only partially dependent on IL-3. Thus, infection with a parasite that induces a "Th2-type response" resulted in accumulation of tissue basophils, and these cells, stimulated by a non-FcR cross-linking mechanism, are a principal source of in vivo IL-4 production.
Current Biology, 1998
Allergens and infections with parasitic helminths preferentially induce Th2 immune responses associated with elevated levels of serum immunoglobulin E (IgE) and expansion of eosinophils and mast cells. Interleukin-4 (IL-4) is a key cytokine in the differentiation of naive CD4 + T cells into Th2 cells, which produce a panel of cytokines including IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 [1] and have been shown to trigger recovery from gastrointestinal nematodes [2]. Nonetheless, mice deficient for IL-4 have been shown to develop residual Th2 responses [3-5] and can expel the nematode Nippostrongylus brasiliensis [6], suggesting that there is a functional equivalent of IL-4 in these processes. IL-13 is a cytokine that shares some, but not all, biological activities with IL-4 [7,8]. There is now compelling evidence that IL-4 and IL-13 share receptor components, including IL-4Ra and IL-13Ra1 [9]. In order to dissect the roles of IL-4 and IL-13 in the regulation of Th2 cells and in the response to nematode infections, we looked for differences between mice deficient for either the IL-4 gene or the IL-4Ra gene. Unlike IL-4, IL-4Ra was required for control of N. brasiliensis, and Th2 development during infection-as characterized by cytokine production, GATA-3 and surface CD30 expression-was more severely affected in IL-4Ra-/mice than in IL-4-/mice. Injection of recombinant IL-13 induced worm expulsion in otherwise incompetent RAG2-/mice. Our results suggest that IL-13 regulates Th2 responses to nematode infection and requires IL-4Ra.