Abstract
The pathogenesis of cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is dictated mainly by the immune-mediated-tissue inflammation developed. The understanding of the immunological mechanisms that generate tissue damage or resolution of lesions is the key to the development of effective vaccine protocols and proper therapeutic schemes. It is clear that the specific immune response mediated by T cells is responsible for the beneficial outcome of the disease, however, the roles of CD4+ T, CD8+ T, NK and NKT cell subpopulations in immunopathogenesis of CL need to be elucidated. Peripheral blood cells from patients before, during and after the antimonial therapy, as well as healthy individuals (HI) were cultured with (LbAgS) or without (NS) L. braziliensis antigens (LbAg). Afterwards, the frequencies of LbAg-specific-cytotoxic CD8+ T, CD4+ T, NK and CD3+CD56+ NKT cells, as well as their activation and exhaustion profiles, were defined by flow cytometry. We observed higher frequencies of CD8+ T, NK and CD3+CD56+ NKT cells and lower frequencies of CD4+ T lymphocytes in LbAgS cell cultures from patients before treatment. The specific response to LbAg resulted in an expansion of cytotoxic-activated CD4+ T, CD8+ T, and NK cells, before and during treatment, indicating specificity in the response by these cells against L. braziliensis. Furthermore, comparing the differences of frequencies of cytotoxic-activated CD4+T, CD8+T, and NK cells, among before and during treatment patients and HI groups, we conclude that these cell populations are in charge of immune response elicited by antimonial therapy. Interestingly, we also observed that NK cells were induced by LbAg to an exhaustion profile during all clinical stages of the disease. The increased antigen-specific activation and cytotoxic activity are in line with the strong inflammatory response described in this disease, a likely cause of tissue damage. These findings reinforce the involvement of these distinct cytotoxic-activated cell populations in the immunopathogenesis of CL, showing a character of specificity in this immune response.
Highlights
Cutaneous leishmaniasis (CL) is a group of neglected diseases initiated through the bite of an infected female sand fly vector, with one million cases reported in the last five years worldwide [1]
Corroborating this statement, we reported the greatest contribution of CD4negCD8neg T cells and NKT in the cytotoxic events in the CL lesion’s milieu [20]
Montenegro skin test (MST) was positive in all patients who were submitted to the test and it was not performed in the healthy individuals (HI) group
Summary
Cutaneous leishmaniasis (CL) is a group of neglected diseases initiated through the bite of an infected female sand fly vector, with one million cases reported in the last five years worldwide [1]. It is important to state that these studies have been focused only in classical-cytotoxic-CD8+ T cells, other cell populations as NK, NKT, and even CD4+ T cells, with cytotoxic profiles, contribute importantly in the immune response in the CL patients, highlighting the important cytotoxic role performed by CD4+ T and NKT cells [19]. Corroborating this statement, we reported the greatest contribution of CD4negCD8neg T cells and NKT in the cytotoxic events in the CL lesion’s milieu [20]. Due this pluri-cell-populations immune response, it is fundamental to investigate the contributions of these cell populations presenting antigenspecific cytotoxicity (CD107a+) [18, 21,22,23], activation (CD38+) [24] and exhaustion (CD279+) [25,26,27,28] profiles
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