Helper T cell subset induction was examined within a single inbred strain of mouse (B10.D2/n) where individuals varied in their ability to expel the nematode parasite Trichuris muris. In this mouse strain approximately half of infected individuals resist infection whilst half are unable to expel the parasite and harbour chronic mature adult worm infections. We here assess various T cell and serological parameters in individual B10.D2/n mice infected with T. muris in relation to the number of parasites harboured. Worm burdens showed very significant negative correlations with five different parameters indicative of the selective expansion within the host of helper T cells of the Th2 subset. Thus, in vitro IL-5 and IL-9 production by restimulated mesenteric lymph node cells, total IgE levels, the early parasite-specific IgG1 response (all P < 0.01) and intestinal eosinophilia (P < 0.05), were all significantly negatively correlated with worm burden. In addition, levels of IL-3 were significantly greater in mice resistant to infection (P < 0.01). In contrast there was a significant positive correlation between worm burden and parasite-specific IgG2a levels (P < 0.05), IgG2a production being under the tight control of the Th1-specific cytokine IFN-gamma and thus a reliable marker for in vivo Th1 cell activation. The data demonstrates that an individual infected with T. muris is capable of mounting either a protective Th2-type response or an inappropriate Th1-type response.(ABSTRACT TRUNCATED AT 250 WORDS)

In murine models of Schistosoma mansoni infection, egg production is associated with a switch from T helper cell (Th)1- to Th2-type responses to both schistosome-specific and unrelated antigens. Polyparasitism is common in human populations within S. mansoni endemic areas. We have, therefore, examined whether coinfection with S. mansoni could affect the outcome of a second parasitic infection, through Th2 cytokine-dependent modifications to the host immune response. We find that when mice susceptible to infection with the gut nematode Trichuris muris are coinfected with S. mansoni, they acquire the capacity to resolve T. muris infection, thus demonstrating a resistant phenotype. This ability to expel T. muris is associated with the production of Th2-associated cytokines, and corresponding antibody isotypes, in response to S. mansoni egg antigens. The Th2 response shows that there is no compartmentalization between spleen and mesenteric lymph nodes, and that the expulsion of T. muris is not caused by any changes in the host intestine associated with excretion of schistosome eggs. This influence of schistosome infections may be important, not only for the outcome of infections with unrelated pathogens in endemic areas, but also for the efficacy of vaccines in such areas.

Mice infected with Trichinella spiralis developed significant enteropathy, comprising villus atrophy, crypt hyperplasia, goblet cell hyperplasia and a decrease in intra-epithelial lymphocyte numbers by 10 days post-infection, when most of the parasites had been expelled from the gut. However, worm expulsion was prevented by treatment with cyclosporin A and, despite a continued parasite burden, cyclosporin A treated animals had no villus atrophy or changes in inflammatory cell numbers. These results confirm that the expulsion of T. spiralis from the mouse gut is accompanied by a significant intestinal lesion and that both of these phenomena are T-cell mediated.

Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR + ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.

Cellular and cytokine responses to infection with Eimeria vermiformis were compared in BALB/c (resistant) and C57BL/6 (B6-susceptible) inbred mice. Cellular responses in the mesenteric lymph node (MLN) occurred sooner after primary infection in the resistant BALB/c strain. In contrast, proliferative responses occurred earlier after challenge in B6 mice. Resting levels of CD4 + ve and CD8 + ve T-lymphocytes in the MLN differed between the two strains but the relative numbers of each subset remained relatively constant throughout primary infection. MLN cells taken at intervals after infection were assayed for release of the cytokines IFN-gamma, IL-5 and IL-10 after culture in vitro with the mitogen Concanavalin A (Con-A) or with parasite antigen. With either stimulus cells from resistant BALB/c mice released IFN-gamma and IL-5 earlier after infection than did B6 cells. The strains had a comparable absolute ability to produce IFN-gamma but BALB/c cells released more IL-5 than did B6, levels declining, rather than increasing, during primary infection in the latter. Only cells from BALB/c mice released IL-10 during infection. Cells taken after a secondary infection released relatively little cytokine after pulsing in vitro. These data suggest that the difference in response phenotype between the two strains when infected with E. vermiformis reflect a kinetic, rather than a qualitative, difference in ability to mount protective T-helper (Th) cell subset responses. No evidence was found for a Th2-mediated interference with ability to release IFN-gamma, the cytokine most closely associated with protective immunity.