Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M. & Sacks, D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502−507

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 41.46). 01/2003; 420(6915):502-7. DOI: 10.1038/nature01152
Source: PubMed


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.

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    • "However, IL-10 promotes pathogen survival by downregulating protective immune responses during infections with Mycobacterium tuberculosis [30], Bordetella pertussis [31], and human immunodeficiency virus (HIV) [32]. The dual role of IL-10 is exemplified in Leishmania major infection, where IL-10 from effector Th1 cells is required to control excessive inflammatory response during acute infection [33], but IL-10 from regulatory T cells contributes to parasite persistence by suppressing effector Th1 cells during chronic infection [34] [35]. "
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    DESCRIPTION: Although it has been established that effector memory CD4+ T cells play an important role in the protective immunity against chronic infections, little is known about the exact mechanisms responsible for their functioning and maintenance, as well as their effects on innate immune cells. Here we review recent data on the role of IFN-γ priming as a mechanism affecting both innate immune cells and effector memory CD4+ T cells. Suboptimal concentrations of IFN-γ are seemingly crucial for the optimization of innate immune cell functions (including phagocytosis and destruction of reminiscent pathogens), as well as for the survival and functioning of effector memory CD4+ T cells. Thus, IFN-γ priming can thus be considered an important bridge between innate and adaptive immunity.
    • "For example, meanwhile C57Bl/6 mice have been shown to be highly susceptible to the experimental induction of organ-specific autoimmune diseases (Graus et al., 1993; Sun et al., 1997; Caspi et al., 1992; Avichezer et al., 2003), Balb/c mice usually display increased susceptibility to spontaneous and induced tumorigenesis (Ullrich et al., 1996; Medina, 1974; Kuraguchi et al., 2001). Furthermore, when infected by the intracellular parasite Leishmania major, C57Bl/6 mice develop protective Th1 immune responses while Balb/c mice show non-protective Th2 responses, being therefore resistant and susceptible strains to the infection, respectively (Reiner and Locksley, 1995; Belkaid et al., 2002). Such immune bias has been shown not only to rely on different MHC haplotypes, but also on profound differences in other key immune components. "
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    ABSTRACT: Antibodies are key immune players in several helminth infections and animal models have been central for the identification of their mechanisms of protection. Murine secondary cystic echinococcosis is a useful model for studying Echinococcus granulosus immunobiology, being the immune profile mounted by the experimental host a determinant of parasite success or failure in infection establishment. In the present study, we analyzed infection outcome using Balb/c and C57Bl/6 mice strains, and compared their antibody responses in terms of quality and intensity. Our results showed that Balb/c is a highly susceptible strain to secondary cystic echinococcosis, while C57Bl/6 mice are quite resistant. Moreover, significant differences between strains were observed in natural and induced antibodies recognizing E. granulosus antigens, both at the systemic and peritoneal levels. Natural cross-reacting IgM, IgG2b and IgG3 antibodies were detected in sera from both strains but with different intensities, and - remarkably - natural IgG2b showed to be an intrinsic correlate of protection in both mice strains. Interestingly, naïve C57Bl/6 serum displayed a higher protoscolicidal activity, and heterologous - but not homologous - transference of C57Bl/6 naïve serum into Balb/c mice, significantly reduced their infection susceptibility. In the peritoneal cavity, different levels of natural cross-reacting IgM and IgG3 antibodies were detected in both mice strains, while cross-reacting IgG2b was detected only in C57Bl/6 mice. On the other hand, infected mice from both strains developed isotype-mixed antibody responses, with Balb/c mice biasing their response towards high avidity IgG1 and C57Bl/6 mice showing a predominance of mixed IgM/IgG2c/IgG2b/IgG3. In this regard, IgG1 levels showed to be a correlate of susceptibility in both mice strains. In conclusion, our results suggest that antibodies - either natural or induced - play a role in the susceptibility degree to murine secondary cystic echinococcosis. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Immunobiology 07/2015; 221(1). DOI:10.1016/j.imbio.2015.07.016 · 3.04 Impact Factor
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    • "However, the precise role of Treg during infection has been discussed controversially. Some studies suggested that Tregs might impair protective antiviral immunity (Lund et al., 2008), whereas others showed that these cells minimized tissue damage (Belkaid et al., 2002; Rouse and Suvas, 2007). In the skin, signaling via the receptor activator of NF-κB (RANK) and its ligand (RANKL) is crucial for the peripheral expansion of Tregs, as shown in a mouse model with epidermal RANKL overexpression (K14-RANKL TG mice) (Loser et al., 2006). "
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    ABSTRACT: Herpes simplex virus-type 1 (HSV-1) causes the majority of cutaneous viral infections. Viral infections are controlled by the immune system and CD8(+) cytotoxic T-lymphocytes (CTLs) have been shown to be crucial during the clearance of HSV-1 infections. Although epidermal Langerhans cells (LCs) are the first dendritic cells (DCs) getting into contact with the virus it has been shown that the processing of viral antigens and the differentiation of anti-viral CTLs is mediated by migratory CD103(+) dermal DCs and CD8α(+) lymph node-resident DCs. In vivo regulatory T-cells (Tregs) are implicated in the regulation of anti-viral immunity and we have shown that signaling via the receptor activator of NF-κB (RANK) and its ligand RANKL mediates the peripheral expansion of Tregs. However, in addition to expanding Tregs RANK-RANKL interactions are involved in the control of anti-microbial immunity by up-regulating the priming of CD4(+) effector T-cells in LCMV infection or the generation of parasite-specific CD8(+) T-cells in Trypanosoma cruzi infection. Here, we demonstrate that cutaneous RANK-RANKL signaling is critical for the induction of CD8-mediated anti-viral immune responses during HSV-1 infection of the skin by preventing virus-induced LC apoptosis, improving antigen-transport to regional lymph nodes and increasing the CTL priming capacity of lymph node DCs.Journal of Investigative Dermatology accepted article preview online, 15 June 2015. doi:10.1038/jid.2015.225.
    Journal of Investigative Dermatology 06/2015; DOI:10.1038/jid.2015.225 · 7.22 Impact Factor
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