Abstract
One of the major drawbacks limiting the use of synthetic peptide vaccines in genetically distinct populations is the fact that different epitopes are recognized by T cells from individuals displaying distinct major histocompatibility complex molecules. Immunization of mice with peptide (181-195) from the immunodominant 43 kDa glycoprotein of Paracoccidioides brasiliensis (gp43), the causative agent of Paracoccidioidomycosis (PCM), conferred protection against infectious challenge by the fungus. To identify immunodominant and potentially protective human T-cell epitopes in gp43, we used the TEPITOPE algorithm to select peptide sequences that would most likely bind multiple HLA-DR molecules and tested their recognition by T cells from sensitized individuals. The 5 most promiscuous peptides were selected from the gp43 sequence and the actual promiscuity of HLA binding was assessed by direct binding assays to 9 prevalent HLA-DR molecules. Synthetic peptides were tested in proliferation assays with peripheral blood mononuclear cells (PBMC) from PCM patients after chemotherapy and healthy controls. PBMC from 14 of 19 patients recognized at least one of the promiscuous peptides, whereas none of the healthy controls recognized the gp43 promiscuous peptides. Peptide gp43(180-194) was recognized by 53% of patients, whereas the other promiscuous gp43 peptides were recognized by 32% to 47% of patients. The frequency of peptide binding and peptide recognition correlated with the promiscuity of HLA-DR binding, as determined by TEPITOPE analysis. In silico prediction of promiscuous epitopes led to the identification of naturally immunodominant epitopes recognized by PBMC from a significant proportion of a genetically heterogeneous patient population exposed to P. brasiliensis. The combination of several such epitopes may increase the frequency of positive responses and allow the immunization of genetically distinct populations.
Highlights
Recent advances in peptide biochemistry and immunochemistry have led to the development of protective antimicrobial vaccines based on synthetic peptides and defined epitopes
In silico analysis of P. brasiliensis gp[43] glycoprotein in search of promiscuous peptides binding to different human leukocyte antigen (HLA)-DR alleles led us to the identification of several immunodominant epitopes recognized by primary CD4+ T cells from treated and healed PCM patients
We observed that the frequency of peptide binding and recognition was commensurate with the promiscuity of HLA binding as determined by TEPITOPE analysis
Summary
Recent advances in peptide biochemistry and immunochemistry have led to the development of protective antimicrobial vaccines based on synthetic peptides and defined epitopes. The central event in the adaptive immune response to invasive microorganisms is the specific recognition of intracellularly processed foreign antigenic peptides bound to the peptide-binding region of the human leukocyte antigen (HLA) class II molecules on the surface of antigen-presenting cells by the T-cell receptor of CD4+ T cells. This is followed by activation, proliferation, and differentiation of specific CD4+ T cells to effector cells that are fully capable of interacting with other inflammatory cells and inducing specialized effector immune responses. It is unlikely that T cells from large proportions
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