Naturally Occurring CD4+Foxp3+ Regulatory T Cells Are an Essential, IL-10-Independent Part of the Immunoregulatory Network inSchistosoma mansoniEgg-Induced Inflammation

Abstract

In acute and chronic schistosomiasis, survival of the host requires a carefully balanced immune response against highly immunogenic parasite eggs. We characterized the phenotype, distribution, and functional role of CD4+Foxp3+ naturally occurring regulatory T cells (naTregs) in schistosome egg-induced inflammation. In adoptive transfer experiments and by intracellular staining for Foxp3, we demonstrate significant frequencies of naTregs in hepatic granulomas and draining lymphoid tissues of mice infected with the trematode Schistosoma mansoni. Strikingly, egg-induced inflammation does not change the normal ratio between naTregs and effector CD4+ T cells at the inflammatory site or in lymphoid organs in acute or chronic disease. However, increasing frequencies of CD103-expressing cells in the naTreg compartment indicate a change in phenotype for naTregs with disease progression. Because CD103 was described recently as an activation marker for naTregs, we speculate that naTregs in chronic schistosomiasis are potentially more suppressive. Furthermore, we found that most naTregs do not contribute to egg-induced IL-4 and IL-10 production. Importantly, depletion of CD25+ naTregs strongly enhances the frequency of IL-4-producing effector T cells in acute egg-induced inflammation. It does not change clonal expansion of activated CD4+ T cells. This regulation of egg-induced cytokine production does not require the presence of IL-10. These data demonstrate that naTregs limit egg-induced effector-cytokine production in our model. Our results identify naTregs as an important, IL-10-independent part of the regulatory network in schistosome egg-induced inflammation.

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

“…These data are in line with a study demonstrating a more pronounced Th2 response in mice infected with the intestinal nematode Trichinella spiralis after removal of Treg by treatment with anti-CD25 Ab [19]. Studies using anti-CD25 Ab during filarial and schistosome infections also report on increased cytokine responses [15,16,18,24,31]. On the contrary, it has been shown recently that anti-CD25 Ab treatment during acute T. gondii infection impairs effector T-cell responses [26].…”

“…We and others have shown that Treg produce IL-10 in a parasite-specific manner and thereby contribute to the antiinflammatory cytokine response seen as a hallmark of nematode infections [21,31,32]. However, studies with Schistosoma mansoni-infected mice clearly showed that effector T cells are the dominant source of IL-10 during infection [18,[31][32][33]. Our current study suggests that non-Treg are the dominant source of IL-10 during intestinal nematode infections.…”

“…There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].In a previous study we observed quantitative and qualitative changes in Treg subsets in mice infected with Heligmosomoides polygyrus bakeri. Treg derived from infected mice displayed an activated phenotype, parasite-specificity and an extraordinary strong suppressive activity on conventional T cells [21].…”

“…We addressed these questions via the specific depletion of Treg in H. p. bakeri-infected mice. To date, Treg depletion or inactivation in parasitic infections was achieved by application of Ab against the surface marker CD25 [18,19,[22][23][24], but there is evidence for an incomplete depletion of Treg by anti-CD25 Ab treatment [22,25]. Furthermore, not only Treg, but also activated T cells transiently express CD25 and may thereby be affected.…”

“…There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].…”