CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

Abstract

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4+CD25+Foxp3+ and CD4+CD25−Foxp3− T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25−Foxp3− T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag−/− reconstituted mice. Surprisingly, Rag−/− mice reconstituted with naive CD4+ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection.

Interleukin-10 from T Cells, but Not Macrophages and Granulocytes, Is Required for Chronic Disease in Leishmania mexicana Infection

“…The fact that macrophages can produce IL-10 in response to parasite immune complexes (at least in vitro) and yet are not sufficient or necessary for chronic disease in this system suggests either an in vivo blockade of this pathway (perhaps due to a lack of Toll-like receptor [TLR] signaling) or that close proximity of the IL-10-producing T cells providing a cell surface marker and/or cytokine is also required. Similar findings have been reported for chronic L. major Seidman infection of B6 mice, in which innate cells produce IL-10, which is not important, whereas IL-10 from T cells is important (21).…”

“…However, because macrophages express Fc␥RI as well as Fc␥RIII and secrete IL-10 in response to IgG1 and IgG2a/c, there was circumstantial evidence that cells other than macrophages might be responsible for the critical IL-10 production that suppresses a needed Th1 response. In addition, IL-10 from T cells has important roles in other Leishmania infections (18)(19)(20)(21)(22). I have now presented direct data showing that T cell IL-10, but not macrophage (or granulocyte) IL-10, is required for chronic disease in murine L. mexicana infection.…”

“…Unfortunately, cells from footpad lesions are not easily assessed. In L. major infection, IL-10 from CD25 ϩ Foxp3 ϩ T reg cells and IL-10 from CD4 ϩ CD25 Ϫ Foxp3 Ϫ IFN-␥ ϩ cells each play a role (19,21,31). Whether L. mexicana infection has similar CD4 ϩ CD25 Ϫ Foxp3 Ϫ T cells has not yet been determined.…”

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

“…Recent work has highlighted a role for IL-27 in the suppression of Th2 development of naïve T cells and Th2 cytokine production by polarized Th2 cells by upregulating the expression of the Th1 transcription factor T-bet and simultaneously downregulating GATA3, essential for the Th2 response [37,38]. As the effects of IL-27/gp130 signalling occur earlier in the infection process and are more direct than the responses driven by the lack of IL-6 and IL-10, the phenotype observed here masks the deleterious effects of uncontrolled IFN-g production by Th1 cells that were shown to be regulated by an autocrine production of IL-10 [39,40]. Even though this hypothesis was demonstrated using Th1 models of infection, we show here that IL-10 À/À mice harbour a high percentage of CD4 1 IFN-g 1 T cells at day 21 p.i., suggesting that the abrogation of the IL-10 negative feedback loop leads to an increase in pathogenic Th1 cells (Fig.…”

Cytokine gene-modulated dendritic cells protect against allergic airway inflammation by inducing IL-10+IFN-γ+CD4+ T cells

“…Recently, another member of the IL-12 family of cytokines, IL-27, was reported to induce IL-10 + IFN-g + T cells, and this phenotype characterizes CD4 + T cells that were described as key negative regulators of the immune response to Toxoplasma gondii and Leishmania major infection. [33][34][35] Actually, IL-10 + CD4 + regulatory cells with a Th1 cell phenotype were described in several infections, including murine Mycobacterium avium and Brucella abortus, as well as in shortterm T-cell clones derived from patients with M. tuberculosis. [36][37][38] However, whether such IL-10 + IFN-g + double-positive T cells as described in these infection models can be defined as Treg or Th1 cells remains to be determined.…”