CD4+CD25+ Regulatory T Cells Restrain Pathogenic Responses during Leishmania amazonensis Infection

Abstract

Although activation of CD4+ T cells mediates pathogenesis in Leishmania amazonensis (La)-infected mice, these susceptible mice do not develop a polarized Th2 response, suggesting a unique mechanism of disease susceptibility. To understand how Th cell activities are regulated, we examined the frequency and phenotypes of regulatory T (Treg) cells. At 1–3 wk of infection, relatively high percentages of CD4+CD25+CD86+ T cells, as well as high levels of FoxP3, TGF-β1, and IL-10RI transcripts, were detected in the skin and draining lymph nodes, indicating local accumulation of Treg cells. Lesion-derived, IL-10-producing CD4+CD25+ cells effectively suppressed proliferation and cytokine (IL-2 and IFN-γ) production of CD4+CD25− effector cells. Adoptive transfer of lesion-derived CD4+CD25+ cells to syngeneic, naive C57BL/6 mice before infection significantly reduced disease development. To further validate the beneficial role of Treg cells in La infection, we adoptively transferred CD25+ T cell-depleted splenocytes (derived from naive mice) into RAG1−/− mice. This transfer rendered RAG1−/− mice more susceptible to La infection than the mice receiving control splenocytes. The beneficial effect of Treg cells was transitory and correlated with decreased activation of IFN-γ-producing effector T cells. This study uncovers an intriguing role of Treg cells in restraining pathogenic responses during nonhealing Leishmania infection and emphasizes a balance between Treg and Th1-like effector cells in determining the outcome of New World cutaneous leishmaniasis.

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

“…In accordance with these reports, we also observed a higher proliferation of CD4 + and CD8 + effector T cells and increased IFN-γ levels in paws from infected P2X7 KO mice. This excessive T cell proliferation might contribute to the pathogenesis in leishmaniasis because CD4 + T cells have a pathogenic role [18], while regulatory T cells have a protective role in this disease [19].…”

“…The Th1/Th2 dichotomy is not observed in L. amazonensis infection because a mixed frequency of CD4 + T cells producing IFN-γ and IL-4 is found during the infection [17]. Interestingly, effector CD4 + T cells are associated with disease pathology [18], while regulatory T cells are associated with lesion resolution [19].…”

Pathogenic role of B cells and antibodies in murine Leishmania amazonensis infection

“…For detection of intracellular cytokines, DLN cells (1 x 10 6 /ml) were re-stimulated with phorbol myristate acetate (PMA)/ionomycin in the presence of GolgiPlug™ (BD Biosciences) for 6 h. Subsequently, cells were stained for surface antigens, fixed/permeabilized with a Cytofix/Cytoperm solution (BD Biosciences), and then incubated for 20 min with PEconjugated rat anti-mouse IL-10 (JES5-16E3, eBioscience) and FITC-conjugated rat antimouse IFN-γ (XMG1.2, eBioscience). For the analysis of lesion-derived CD4 + T cells, tissues of infected mice were processed as previously described (Ji et al, 2005), with some modifications. Briefly, the soft foot tissue of 3-week infected mice were harvested, cut and torn into small pieces by forceps.…”

Intralesional Regulatory T-Cell Suppressive Function during Human Acute and Chronic Cutaneous Leishmaniasis Due to Leishmania guyanensis

“…In addition, in a model of CCL due to infection with L. major, it has been shown that Treg cells accumulate at the site of infection, rendering the Th1 response induced by infection with the L. major Sd strain ineffective (1). Treg cells were also shown to limit immunopathogenesis caused by L. amazonensis by inhibiting the activities of L. amazonensis-specific effector cells (17). In contrast, in a murine model of infection with L. mexicana, it was recently demonstrated that depletion of CD4 ϩ…”