Heat-shock protein 60 and gamma-delta T cells: Investigations of HSP60 as a potential antigen for gamma-delta T cells in an infectious disease model

γδ T cells were identified as part of the specific immune system nearly 15 years ago, yet their immuniological role and the ligand recognized by the γδ TCR have yet to be determined. Studies to determine the antigen for γδ T cells have been varied and disparate, indicating that the cells can respond to whole proteins, to small phosphorylated molecules, and to heat shock protein 60 (hsp60). The structure of the hsp60 complex as a ring in which protein folding occurs may indicate that the ligand for γδ T cells is the hsp60 complex acting as an antigen presenting structure for interior unfolded proteins. Studies conducted in this thesis investigate hsp60/protein complexes as ligands for the γδ TCR using the infectious disease model of infection of mice with the intracellular bacteria Listeria monocytogenes (Lm). During Lm infection, γδ T cells predominantly express potentially hsp60-reactive Vδ6 and Vδ4 T cell receptors. Additionally, cells expressing the Vδ6 TCR display an activated phenotype. Increases in expression of cell surface murine hsp60 during infection correlate with increased γδ T cell numbers. Investigations of the responses of γδ T cells to hsp60 and hsp60/protein complexes reveal that γδ T cell hybridomas are an ineffective cell system for studying γδ T cell responses. However, stimulation of γδ T cells isolated directly from infected animals indicates that γδ T cells may indeed be responding to hsp60 with an accompanying interior protein. These results are complicated by the finding that anti-hsp60 antibody alone can inhibit cytokine production by hsp60+ γδ T cells. A new model is proposed in which γδ T cells respond to hsp60/protein complexes on infected, damaged, or activated cells, while at the same time the hsp60 complex itself modulates a signal to the antigen presenting cells.