Processing and presentation of variant surface glycoprotein to Th cells during African trypanosomiasis.

摘要

Trypanosoma brucei rhodesiense (T. b. rhodesiense ) is a unicellular protozoan parasite and the causative agent of African sleeping sickness, a fatal disease in humans. During infection, B cell and T helper 1 (Th1) cell responses to the trypanosome variant surface glycoprotein (VSG) coat provide temporal protection and contribute to host resistance. Dendritic cells and macrophages activate Th cells by presenting antigenic peptides associated with MHC II molecules at their surface for specific recognition by the T cell receptor (TCR). Preliminary evidence in trypanosomiasis suggests that Th1 cells recognize peptides derived from a conserved amino acid hypervariable region (HV-1) buried within VSG homodimers, but do not recognize peptides derived from other hypervariable or invariant sub-regions of the molecule. We hypothesize that different VSGs are processed in a similar manner by APCs so that only specific peptides from within the conserved HV-1 region are presented for recognition by Th cells. To address this hypothesis, the overall antigen processing and presentation capabilities of APCs were assessed during infection with T. b. rhodesiense. Subsequently, APC presentation of VSG peptides was examined using VSG-specific T cell hybridomas derived from T cells activated during infection by exposure to APCs and VSG peptides. Finally, the VSG peptide specificity of these T cells was defined to elucidate whether VSG-specific Th cells recognized limited regions of the VSG. We determined that dendritic cells from relatively resistant animals undergo maturation and can activate Th cells at a specific time during early infection coincident with the presentation of VSG peptides. Macrophages displayed lesser antigen presentation capabilities and presented fewer VSG peptides at lower levels. These studies demonstrated a role for DCs in the activation of VSG-specific Th1 responses. Mapping of VSG-specific Th cell specificity revealed that Th cell epitopes are located throughout the VSG molecule. Additionally, the defined epitopes did not coincide with a region of amino acid hypervariability predicted to have been selected for by Th cell pressure. These studies are the first to dissect the role of APCs in the VSG-specific T cell activation in African trypanosomiasis.