Endogenous regulatory T cells (Treg) play a central role in the control of excessive or misdirected immune responses against self or foreign Ags. To date, virtually no data are available on the nature of the molecules and signals involved in the trafficking and retention of Treg in tissues where regulation is required. Here, we show that expression of αEβ7 integrin is necessary for the homing of Treg at site of Leishmania major infection. The vast majority of Treg present in the dermis at steady-state conditions or during L. major infection express the αE chain (CD103) of αEβ7. Genetically susceptible BALB/c mice that lack CD103 become resistant to infection, a phenotype that is associated with a poor capacity of Treg to be retained in the infected site. Such susceptible phenotype can be restored when Treg from wild-type mice were transferred in CD103−/− mice. The central role of CD103 in Treg retention was further demonstrated by usage of blocking Abs against CD103 and the transfer of Treg purified from CD103−/− mice. Our results strongly suggest that this molecule is induced and maintained on Treg following or just prior to their arrival in tissues. Furthermore, the expression of CD103 and the subsequent retention of Treg in tissues is highly regulated by their exposure to Leishmania Ag and the level of activation of the APCs they encounter. Thus, CD103, by controlling Treg retention, can contribute to the outcome of chronic infection by Leishmania.

Obligatory intracellular parasites such as Plasmodium sp, Trypanosoma cruzi, Toxoplasma gondii and Leishmania sp are responsible for the infection of hundreds of millions of individuals every year. These parasites can deliver antigens to the host cell cytoplasm that are presented through MHC class I molecules to protective CD8 T cells. The in vivo priming conditions of specific CD8 T cells during natural infection are largely unknown and remain as an area that has been poorly explored. The antiparasitic mechanisms mediated by CD8 T cells include both interferon-γ -dependent and -independent pathways. The fact that CD8 T cells are potent inhibitors of parasitic development prompted many investigators to explore whether induction of these T cells can be a feasible strategy for the development of effective subunit vaccines against these parasitic diseases. Studies performed on experimental models supported the hypothesis that CD8 T cells induced by recombinant viral vectors or DNA vaccines could serve as the basis for human vaccination. Regimens of immunization consisting of two different vectors (heterologous prime-boost) are much more efficient in terms of expansion of protective CD8 T lymphocytes than immunization with a single vector. The results obtained using experimental models have led to clinical vaccination trials that are currently underway.

We evaluated whether four recombinant antigens previously used for vaccination against experimental infection with Leishmania (Leishmania) major could also induce protective immunity against a challenge with Leishmania ( The protozoan parasite Leishmania (Viannia) braziliensis commonly causes localized cutaneous leishmaniasis (CL); however, a chronic mucosal leishmaniasis (ML) may develop in some infected individuals, with severe and progressive manifestations (reviewed in reference 11). At present, this species accounts for more than 90% of the 28,712 annual cases of CL and ML recorded in Brazil in 2004 (7). Although chemotherapies for CL and ML do exist, there are several limitations: (i) drug treatment is rarely affordable by those who need them, (ii) drug treatment requires daily injections of the drug for weeks, (iii) drug treatment can be associated with side effects, and (iv) drug resistance is becoming an increasing problem (13, 24; reviewed in references 3 and 32). To make matters worse, control of CL and ML is problematic due to the sylvatic nature of both vectors and reservoirs, making insecticide spraying and the elimination of reservoirs particularly difficult (26). Due to these difficulties, in the long run, the development of an effective vaccine may help both the prevention and the treatment of CL and ML caused by L. (V.) braziliensis.Most studies conducted thus far in vaccination against CL used genes and/or antigens isolated and characterized from Leishmania (Leishmania) major or L. (L.) amazonensis (8, 31; reviewed in references 9 and 21). Among the leading candidates to the development of a vaccine against CL, there are homologues of the receptor for activated C kinase protein (LACK or p36), Leishmania elongation and initiation factor (LeIF), L. (L.) major stress inducible protein 1 (LmSTI1), and thiol-specific antioxidant (TSA) from L. (L.) major (5, 6, 10, 14, 15, 28, and 30).Based on these promising prospects, the present study was designed to test whether four recombinant antigens previously used for vaccination against experimental infection with L. (L.) major (LACK, LmSTI1, LeIF, and TSA) could also generate protective immunity against an intradermal (i.d.) challenge with L. (V.) braziliensis. We considered this question very important because, as mentioned above, this species is responsible for most cases of CL and ML in Brazil and in the New World.