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.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leishmania parasites can cause visceral or cutaneous disease and are found in subtropical and tropical regions of the Old and New World. The pathology of the infection is determined by both host immune factors and species/strain differences of the parasite. Dogs represent the major reservoir of Leishmania infantum (syn. L. chagasi) and vaccines are considered the most cost-effective control tools for canine disease. Selection of immunodominant peptides was performed by Phage Display to identify sequences recognized by L. infantum naturally infected animals. Sera from Leishmania infected animals were used in the biopanning to selection of specific peptides. Serum samples from T. cruzi infected and healthy animals were used as control. After selection, synthetic peptides were produced in membrane (spot-synthesis) in soluble form and blotting and ELISA were performed for validation of serum reactivity. Selected peptide was formulated with aluminum hydroxide and liposomes and immunization was performed in BALB/c mice. Protection was determined by qPCR after challenge infection with virulent L. infantum. We reported the selection of Peptide 5 through Phage Display technique and demonstrate its ability to promote a state of immunity against L. infantum infection in murine model after immunization using liposomes as vaccine carrier. Our results demonstrate that immunization with Peptide 5 when formulated with aluminum hydroxide and liposomes is immunogenic and elicited significant protection associated with the induction of mixed Th1/Th2 immune response against L. infantum infection. Peptide 5 is a promising vaccine candidate and the findings obtained in the present study encourage canine trials to confirm the effectiveness of a vaccine against CVL.
    Parasites & Vectors 03/2015; 8(1). DOI:10.1186/s13071-015-0747-z · 3.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human diseases caused by protozoan parasites are renowned for their high rates of morbidity and mortality worldwide. Some examples include African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease, leishmaniases, malaria and babesiosis. These infections tend to follow a chronic rather than an acute course with lifelong persistence of parasites. Regulatory T cells (Treg), in particular the CD4 + CD25 + cell subset, appear to control the immune competence of host response triggered by the presence of parasites, promoting homeostasis and protecting the host from collateral tissue damage whilst allowing parasite persistence. To date, there is still considerable controversy on the characteristics and function of these cells when induced during different protozoan infections, evidencing the need of further research. Therefore, this review aims to provide a comprehensive overview about Treg cells development, phenotype determination and general functions. The above pathologies were used as selected examples to discuss the role of Treg cells during protozoan infections. Understanding of the mechanisms that contribute towards homeostasis and the survival of the host, and simultaneously allow the persistence of the pathogen, may yield important insights for new strategies of prophylaxis and therapy.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Treg cells are key elements of the immune system which are responsible for the immune suppressive phenotype of cancer patients. Interaction of Treg cells with conventional anticancer therapies might fundamentally influence cancer therapy response rates. Radiotherapy, apart of its direct tumor cell killing potential has a contradictory effect on the antitumor immune response: it augments certain immune parameters, while it depresses others. Treg cells are intrinsically radioresistant due to reduced apoptosis and increased proliferation, which leads to their systemic and/or intratumoral enrichment. While physiologically Treg suppression is not enhanced by irradiation, this is not the case in a tumorous environment, where Tregs acquire a highly suppressive phenotype, which is further increased by radiotherapy. This is the reason why the interest for combined radiotherapy and immunotherapy approaches focusing on the abrogation of Treg suppression increased in cancer therapy in the last few years. Here we summarize the basic mechanisms of Treg radiation response both in healthy and in cancerous environment and discuss Treg-targeted pre-clinical and clinical immunotherapy approaches used in combination with radiotherapy. Finally, the discrepant findings regarding the predictive value of Tregs in therapy response are also reviewed. Copyright © 2015. Published by Elsevier Ireland Ltd.