Interleukin-4-Promoted T Helper 2 Responses EnhanceNippostrongylus brasiliensis-Induced Pulmonary Pathology

Abstract

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. T helper type 2 (TH2) immune effector responses are characterized by interleukin-4 (IL-4)-and IL-13-dependent signaling through heterodimeric receptors containing an IL-4 receptor alpha (IL-4R␣) subunit (3). These effector responses are particularly associated with the resolution of helminth infections (16,32,34) and the induction of allergic reactions (12). IL-4R␣ signaling results in activation and upregulation of the transcription factors STAT-6 and GATA-3, which stabilize the TH2 program in polarized CD4 ϩ T cells (3, 27). CD4 ϩ T-cell IL-4R␣-dependent TH2 differentiation is considered to be specific to IL-4, as T cells lack functional IL-13 receptors (43). The resulting TH2 response is characterized by B-cell immunoglobulin E (IgE) and IgG1 antibody production (4, 37), goblet cell hyperplasia (17), and secretion of the TH2 cytokines IL-4, IL-13, IL-5, IL-10, and IL-9 by a number of hematopoietic cells (26). CD4 ϩ T-cell populations and IL-4R␣ expression are essential for the optimal development of TH2 responses (16). However, no requirement for IL-4R␣ expression in T-cell subpopulations for the development of a TH2 response has been demonstrated. Indeed, the interesting observation that there is CD4 ϩ T-cell IL-4R␣-independent IL-4 and IL-13 production has been widely reported (8,15,23,29,31,40). Thus, IL-4-responsive CD4ϩ T cells may not be essential for TH2 polarization (20). In order to examine this possibility, we generated CD4 ϩ T-cell IL-4R␣ transgenic mice with 95.5% Ϯ 5.8% disruption of IL-4R␣ expression on CD4 ϩ T cells (CD4 ϩ T-cell IL-4R␣ knockout [KO] mice) (30). Infection of these mice with Leishmania major indicated that non-IL-4-responsive CD4 ϩ T cells can launch aspects of a TH2 response (30). Additionally, in ovalbumin-induced anaphylaxis (a TH2-associated pathology) T-cell TH2 cytokine secretion appears to be unaffected by IL-4R␣ CD4 ϩ T-cell expression (28). Together, these findings demonstrate that IL-4R␣ expression on CD4 ϩ T cells is not essential for generation of a TH2 immune response.In the study described here we further defined the roles of IL-4-responsive CD4 ϩ T cells by infecting CD4 ϩ T-cell IL-4R␣ KO mice with the nematode Nippostrongylus brasiliensis. N. brasiliensis infections are characterized by a striking IL-4R␣-driven TH2 polarized host immune response which is essential for expulsion of adult worms from the host intestine (35). Importantly, N. brasiliensis infections are analogous to human hookworm infections (e.g., Necator americanus and Ancylostoma duodena...

Nippostrongylus-Induced Intestinal Hypercontractility Requires IL-4 Receptor Alpha-Responsiveness by T Cells in Mice

“…In contrast, T cell-specific IL-4Rα deficient mice showed impaired IL-4 and IL-13 cytokine response of equivalent magnitude to IL-4Rα −/− mice. These results are supported by our previous study where mediastinal lymph node CD4 + T cells from mice lacking IL-4Rα expression specifically on CD4 + T cells (Lck cre IL-4Rα −/lox ) maintained their ability to produce IL-13 in contrast to the CD4 + T cells isolated from digested lung [28]. Together these results demonstrate impaired IL-4 production by mesenteric CD4 + T cells and impaired IL-4 and IL-13 levels in the jejunum of N. brasiliensis -infected T cell-specific IL-4Rα deficient mice.…”

“…As previously demonstrated, IL-4Rα −/− mice did not clear infection efficiently showing a maintained egg production at day 11 PI and the presence of adult worms detected at day 10 PI [20], [24]. As seen in previously described CD4 + T cell-specific IL-4Rα deficient mice (Lck cre IL-4Rα −/lox ) [28], pan T cell-specific IL-4Rα deficient mice efficiently clear the worms similar to IL-4Rα-responsive control mice.…”

“…Our previous studies have shown that the expression of IL-4Rα specifically on CD4 + T cells and macrophage/neutrophils is not required for N. brasiliensis expulsion [24], [28]. In this study, we used recently established pan (CD4 + , CD8 + , NK T and γδ) T cell-specific IL-4Rα (iLck cre IL-4Rα −/lox ) deficient mice [29] and demonstrated that IL-4Rα expression by T cells is also not required for worm expulsion.…”

Genes associated with alternatively activated macrophages discretely regulate helminth infection and pathogenesis in experimental mouse models

“…Whether this phenotype is entirely driven by AAM remains to be fully defined as other work has shown that mice deficient for IL-4Ra expression on macrophages resolve N. brasiliensis infections normally (Herbert et al, 2004). N. brasiliensis infection, also causes severe pulmonary pathologies in the host, which are initially analogous to asthma and later develop into an emphysema-like disease (Marsland et al, 2008;Mearns et al, 2008;Reece et al, 2008;Siracusa et al, 2008). Here it has been shown that pulmonary AAMs have an elevated expression of MHCII and other co-stimulatory molecules and increased levels of antigen uptake and processing .…”

“…This acute infection is typically resolved within 9 days following infection. Immunologically N. brasiliensis infection results in the generation of a highly polarised TH2 response (Barner et al, 1998;Mearns et al, 2008) with IL-4 and IL-13 driving the induction of AAMs in the lung and intestine Siracusa et al, 2008;Zhao et al, 2003Zhao et al, , 2008. Functionally it has been shown that Table 1 Summary of helminth associated AAM function.…”