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.

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    ABSTRACT: Introduction: Human Leishmaniasis is distributed worldwide and is mainly in the tropics and subtropics, with a prevalence of 12 million cases and an approximately incidence of 0.5 million cases of visceral Leishmaniasis(VL) and 1.5 million cases of cutaneous Leishmaniasis (CL). Leishmania parasites are vector-born protozoan pathogens found in tropical and subtropical regions of both the old and new world. The disease in human can be divided into cutaneous, visceral, and mucosal syndromes. The aim of this study was to conduct further studies over our new formulation of Leishmania major vaccine which experimentally had satisfactory results. Method: For the detail of the procedure it is referred to the author’s previous publications. Briefly one hundred and twenty Balb/c mice were randomly divided into four groups as LT, LB, LBT and control groups. Groups LT, LB and LBT injected subcutaneously with the antigen and the same booster doses with a week interval. The expansion rates of the spleen white pulp size was evaluated and the levels of the serum TH1 (IFN-γ, IL-12) and TH2 (IL-4, IL-10) cytokines measured with the ELISA method. Results: Comparing to the LT and LB groups, the LBT group had highest levels of serum IL-12, lowest levels of IL-10 and highest increase in the spleen white pulp size. Significant negative correlation was observed between IL-12 and IL-10 but not IFN-γ or IL-4. Conclusion: The present study indicated that the LBT group which received crude cocktail Leishmania antigen plus alcoholic extract of Teucrium polium and BCG as adjuvants showed satisfactory cytokines profile comparing to groups LT and LB, since highest levels of IL-12 and lower levels of IL-10 could help the infected subjects to inhibit or eradicate the intracellular Leishmania amastigotes, and also highest increase in the spleen white pulp size which pointed to the synergistic effects of BCG and alcoholic extract of T. polium.
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  • PLoS Pathogens 12/2014; 10(12):e1004456. · 8.14 Impact Factor
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    ABSTRACT: In contrast to the ability of long-lived CD8+ memory T cells to mediate protection against systemic viral infections, the relationship between CD4+ T cell memory and acquired resistance against infectious pathogens remains poorly defined. This is especially true for T helper 1 (Th1) concomitant immunity, in which protection against reinfection coincides with a persisting primary infection. In these situations, pre-existing effector CD4 T cells generated by ongoing chronic infection, not memory cells, may be essential for protection against reinfection. We present a systematic study of the tissue homing properties, functionality, and life span of subsets of memory and effector CD4 T cells activated in the setting of chronic Leishmania major infection in resistant C57Bl/6 mice. We found that pre-existing, CD44+CD62L-T-bet+Ly6C+ effector (TEFF) cells that are short-lived in the absence of infection and are not derived from memory cells reactivated by secondary challenge, mediate concomitant immunity. Upon adoptive transfer and challenge, non-dividing Ly6C+ TEFF cells preferentially homed to the skin, released IFN-γ, and conferred protection as compared to CD44+CD62L-Ly6C- effector memory or CD44+CD62L+Ly6C- central memory cells. During chronic infection, Ly6C+ TEFF cells were maintained at high frequencies via reactivation of TCM and the TEFF themselves. The lack of effective vaccines for many chronic diseases may be because protection against infectious challenge requires the maintenance of pre-existing TEFF cells, and is therefore not amenable to conventional, memory inducing, vaccination strategies.
    PLoS Pathogens 12/2014; 10(12):e1004538. · 8.14 Impact Factor