HLA Class I–Restricted T Cell Epitopes of the Kinetoplastid Membrane Protein–11 Presented byLeishmania donovani–Infected Human Macrophages

Abstract

Visceral leishmaniasis is a protozoal disease caused by the intracellular parasites Leishmania donovani and L. chagasi/infantum, and it is usually deadly if not treated. To date, no vaccine exists for prophylaxis or immunotherapy, nor has it been established which effector mechanisms of the immune system are most instrumental against the parasites. Recent reports have suggested that CD8(+) T cells, in addition to CD4(+) T cells, might play major roles in the defense against infection and in the cure of the disease. To identify epitopes recognized by CD8(+) T cells that can be used for immune monitoring to investigate the role of these cells in human visceral leishmaniasis, as well as in vaccine development, we scanned the entire sequence of the leishmanial protein kinetoplastid membrane protein (kmp)-11 with overlapping nonapeptides. Thirty peptides that specifically trigger interferon- gamma secretion by human CD8(+) T cells were identified. Four T cell lines with specificities for different peptides recognize Leishmania-infected autologous macrophages, which proves that kmp-11 is processed and presented via the major histocompatibility complex class I pathway of infected cells. Kmp-11 is thus a candidate antigen for the development of T cell vaccines.

Designing Therapies against Experimental Visceral Leishmaniasis by Modulating the Membrane Fluidity of Antigen-Presenting Cells

“…The impact of the decrease in membrane cholesterol on the T-cell-stimulating ability of I-M⌽s was also assessed. Previously, we have shown that L. donovani-infected human monocytes can act as anti-KMP-11 peptide-specific cytotoxic T-lymphocyte targets without exogenous KMP-11 (7). The present study revealed that KMP-11 was expressed in both I-M⌽s and L-I-M⌽s as an endogenous antigen and that the signal was weaker in the former M⌽s.…”

“…We have shown that L. donovaniinfected human monocytes can act as anti-KMP-11 peptidespecific cytotoxic T-lymphocyte targets without exogenous KMP-11 (7). The expression of KMP-11 on splenic I-M⌽s and L-I-M⌽s was therefore studied.…”

Vaccines for Leishmaniasis: From proteome to vaccine candidates

“…The C-terminus in comparison is a lot less represented with one strong binder starting at position 78 and a couple of weak binders. This is coherent with experimental data, since all three experimentally identified clusters (aa 1-33, aa 50-60, aa 70-86) have been retrieved with NetMHC, 50 which indicated clustered binding regions N-terminal (1-30) and C-terminal (71-90). Interestingly, the majority of peptides found, is predicted to bind to the selected HLA-A haplotypes, while the algorithm detected only one weak binder for the chosen HLA-B haplotypes.…”

Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection

“…The success of antileishmanial chemotherapeutics depends on effective T cell-based host immune response (58). Infection with Sb R LD was associated with depressed Ag-specific T cell responses, decreased IL-12, TNF-a, and IFN-g production, and upregulation of suppressive cytokines IL-10 and TGF-b in an animal model of VL (24,28).…”