CD4(+)CD25(+) regulatory T cells control Leishmania major persistence and immunity

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 42.35). 01/2003; 420(6915):502-7. DOI: 10.1038/nature01152
Source: PubMed

ABSTRACT The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.

  • Source
    • "Considering the above and for the reasons that will be mentioned below, we speculate that a population of T reg with memory function is involved in protection against CL. Although antigen specificity of T reg has been addressed in L. major infection [43] [44], little evidence has so far been available to prove the existence of a population of memory T reg . However in recent years, a population of memory T reg has been identified in researches concerning viral infections in which pathogen-specific T reg have been shown to form a memory pool after resolution of the infection [16] [45] [46]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Two groups of residents in an endemic area of Leishmania major infection in Iran with positive leishmanin skin tests who were either asymptomatic or had healed cutaneous leishmaniasis lesions were compared with respect to their T helper responses. The percentages of regulatory T cells (Treg; CD4(+)CD25(high) FoxP3(+)) from the peripheral blood and CD4(+) T cells producing intracellular cytokines (IL-4, IL-10, IL-17 and IFN-γ) from the stimulated PBMCs were evaluated by flow cytometry and the expressions of RORC and FOXP3 genes were quantified by real-time RT-PCR. T responder (CD4(+)CD25(-)) and Treg-enriched (CD4(+)CD25(+)) cells were isolated magnetically and the suppressive capacity of the latter and the cytokines (IFN-γ, TGF-β and IL-10) secreted from them were evaluated by in vitro assays. The results showed that the frequency of Treg in the studied groups were similar and Treg from both groups exhibited high yet similar suppressive capacities while significantly higher levels of FOXP3 expression was observed in the asymptomatic group. Taken together, similar frequency and suppressiveness of Treg combined with high ratios of IFN-γ/IL-10 producing CD4(+) T cells were common in both groups; however the members of the asymptomatic group appeared to require higher expression of FOXP3 to maintain their immunity to re-infection.
    Human Immunology 08/2014; 75(10). DOI:10.1016/j.humimm.2014.08.204 · 2.28 Impact Factor
  • Source
    • "Deficiencies in Foxp3 function result in autoimmunity very early in life in both mice and humans due to a lack of proper immune regulation Brunkow et al., 2001; Bennett et al., 2001. In addition, Tregs have been shown to limit pathogen-specific T cell responses during both acute Ruckwardt et al., 2009; Fulton et al., 2010; Loebbermann et al., 2012; Haeryfar et al., 2005 and chronic infections Belkaid et al., 2002; Schmitz et al., 2013. The vital role of Tregs in immune homeostasis has led to the development of novel tools to further dissect the functions of Tregs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T cells (Tregs) play a critical role in maintaining tissue homeostasis and preventing the development of immunopathology. Depletion of REGulatory T cell (DEREG) mice express a diphtheria toxin receptor (DTR)-eGFP transgene under the control of the Foxp3 promoter allowing for Treg depletion following diphtheria toxin (DT) administration. DEREG mice have been utilized to investigate the role of Tregs in a wide range of disease settings. Administration of DT to naïve DEREG mice resulted in the rapid depletion of Foxp3+ Tregs from the peripheral blood. However, by day 4 post-DT administration, a GFP− Foxp3+ Treg population emerged that lacked expression of the DTR transgene and was resistant to further depletion by additional DT treatment. We further evaluated the impact of Treg depletion during both acute and chronic viral infections. Similar to naïve mice, Treg numbers rapidly rebounded during an inflammatory setting following an acute viral infection. DT treatment of both WT and DEREG mice following both acute and chronic viral infections induced exacerbated disease as compared to PBS-treated controls. Furthermore, following a chronic systemic viral infection, DT treatment resulted in nearly 100 percent mortality in both WT and DEREG mice while the PBS-treated controls survived. Our results demonstrate that Treg depletion in DEREG mice is transient and that DT administration can have adverse effects during virus-induced inflammation and highlights the critical need to include DT-treated WT mice when using DTR models to control for DT-mediated toxicity.
    Journal of immunological methods 04/2014; 406. DOI:10.1016/j.jim.2014.03.005 · 2.01 Impact Factor
  • Source
    • "Tregs produced from the thymus are all naı¨ve-like, but a subset of them quickly acquires the effector/memory-like phenotype after entering secondary lymphoid organs, which occurs as a result of encounters with self-antigens and is presumably essential for peripheral tolerance (Lee et al, 2007). Tregs are subject to an additional layer of regulation in the presence of overt inflammation (due to, e.g., pathogen infection or organ transplant), which can involve Treg activation, expansion, differentiation and trafficking (Belkaid et al, 2002; Suffia et al, 2006; Belkaid and Tarbell, 2009; Zhang et al, 2009). Treg activation is crucial for Treg function both in vitro and in vivo (Takahashi et al, 1998; Thornton and Shevach, 1998; Park et al, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treg activation in response to environmental cues is necessary for regulatory T cells (Tregs) to suppress inflammation, but little is known about the transcription mechanisms controlling Treg activation. We report that despite the known proinflammatory role of the chromatin-remodelling factor BRG1 in CD4 cells, deleting Brg1 in all αβ T cell lineages led to fatal inflammation, which reflected essential roles of BRG1 in Tregs. Brg1 deletion impaired Treg activation, concomitant with the onset of the inflammation. Remarkably, as the inflammation progressed, Tregs became increasingly activated, but the activation levels could not catch up with the severity of inflammation. In vitro assays indicate that BRG1 regulates a subset of TCR target genes including multiple chemokine receptor genes. Finally, using a method that can create littermates bearing either a tissue-specific point mutation or deletion, we found the BRG1 ATPase activity partially dispensable for BRG1 function. Collectively, these data suggest that BRG1 acts in part via remodelling-independent functions to sensitize Tregs to inflammatory cues, thus allowing Tregs to promptly and effectively suppress autoimmunity.
    The EMBO Journal 01/2013; 32(3). DOI:10.1038/emboj.2012.350 · 10.75 Impact Factor
Show more