Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

Abstract

dCutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a strong Th1 response that leads to skin lesion development. In areas where L. braziliensis transmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) than do CL patients, but they are able to control the infection. ؉ T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8 ؉ T cells are more cytotoxic and may be involved in pathology. L eishmaniasis is caused by infection with parasites of the genusLeishmania. Leishmaniasis is a neglected tropical disease; 214,000 new cases of cutaneous leishmaniasis (CL) are reported annually worldwide, and the estimated incidence of leishmaniasis is 690,000 to 1,200,000 cases. Approximately 67,000 cases are reported in South America, Central America, and the Caribbean (1). In mice, the majority of Leishmania-specific CD4 ϩ T cells differentiate into T-helper 1 (Th1) cells that secrete gamma interferon (IFN-␥) and contribute to the elimination of the parasite through the activation of macrophages (2, 3). Although protective immunity has predominantly been related to IFN-␥-producing CD4 ϩ T cells, infection with Leishmania also results in the activation and expansion of parasite-specific CD8 ϩ T cells (4, 5). Human CL caused by Leishmania braziliensis is characterized by a strong Th1 response with the production of high levels of IFN-␥ and tumor necrosis factor alpha (TNF-␣) (6, 7). This exaggerated Th1 response is associated with the development of lesions and the severity of the disease (6, 8-10). In patients with CL caused by L. braziliensis, there are more CD4 ϩ than CD8 ϩ T cells, but this ratio reaches an equilibrium due to the increase in CD8 ϩ T cells that occurs during the healing process (11). The enrichment of Leishmania-reactive CD8 ϩ T cells in older lesions suggests that these cells may play a role in the healing process (12). In contrast, other studies have associated CD8ϩ T cell functions with pathology. For example, the cytotoxicity mediated by CD8 ϩ T cells is greater in mucosal leishmaniasis (ML), a more severe form of L. braziliensis infection, than in CL (13,14). More recently, it was shown that the frequency with which CD8 ϩ T cells express granzyme in the lesions of CL patients is greater than that in patients in the early phase of CL (i.e., before the ulcer has developed) and that the frequency with which CD8 ϩ T cells express granzyme is directly associated with the intensity of the inflammatory reaction observed in CL ulcers (15,16). This controversy regarding the role of cytotoxicity in the pathogenesis of human leishmaniasis indicates that the functions of CD...

Atypical Manifestations of Cutaneous Leishmaniasis in a Region Endemic for Leishmania braziliensis: Clinical, Immunological and Parasitological Aspects

“…Although excessive IFN-γ and cytotoxic CD8 + T cells may contribute to the inflammatory response that leads to ulcer development [37–39], the importance of IFN-γ as a defense mechanism in CL is well established. Suppressed production of IFN-γ is associated with systemic spread of L .…”

A Potential Role for Mononuclear Phagocytes in Cutaneous Ulcer Development in Human Immunodeficiency Virus–Leishmania braziliensis Coinfection

“…Blood was collected and a biopsy was performed for immunological studies. The patient had a viral load of 89,296 copies/mL, CD4 + cell counts of 105 cells/ mm 3 , and CD8 + cell counts of 422 cells/mm 3 . Antiretroviral therapy with tenofovir, lamivudine, and efavirenz was started.…”

“…In November 2013, the patient returned for follow-up, and total scar formation was observed in the lesion. At this time the patient presented with undetected viral load, CD4 and CD8 cell counts of 171 and 409 cells/mm 3 , respectively. Immunological results.…”

“…[3][4][5][6] Human immunodeficiency virus (HIV) infection leads to a decrease in CD4 + T cell count, increasing the risk for opportunistic disease progression. 7 Coinfection with HIV and L. braziliensis has been reported, and the clinical aspects include large and multiple ulcers as well as mucosal involvement.…”

Expression of annexin A1 in Leishmania-infected skin and its correlation with histopathological features

“…For instance, hyperinfl ammatory collateral damage from T helper type 1 (Th1) response has been reported, along with a variable T helper type 2 (Th2) response dependent on cytokine release and other T cells (12) (13) . Moreover, Cardoso et al (14) demonstrated that cluster of differentiation 8 (CD8) + T cells in patients with subclinical Leishmania braziliensis infection secrete interferon gamma (IFN-γ) to activate macrophages and facilitate parasite clearance. Notably, Pereira-Carvalho et al (15) showed that T cells maintain activation levels at approximately 2 years after the end of therapy, and lymphocytes from well-healed lesions recognize leishmanial stimuli and proliferate upon exposure.…”