The overall hypothesis of this unit is that regulatory mechanisms of the endocytic pathway are critical in influencing the effective expression of TCR and class I and II MHC molecules during ontogeny and infection. Some of these regulatory mechanisms are predicted to be specific to human cells. Therefore, to have the greatest impact on understanding human disease, these studies on the immune function of the endocytic pathway will be carried out using cells derived from human tissue and blood.
The specific aims of this unit focuses on how the endocytic pathway controls expression of either TCR or MHC molecules during the development and stimulation of an immune response.
Each aim represents a collaboration with at least one other investigator in the program. The experiments proposed draw upon a combination of principal investigators expertise in the cell biology of endocytosis and antigen presentation with the expertise of the other four investigators in studying lymphoid and myeloid cell development, activation, and infection.
The specific aims are as follows.
Aim 1 will define mechanisms of TCR modulation during ontogeny and activation. The hypothesis that TCR down-regulation upon antigenic stimulation is a function of signaling-induced stimulation of receptor-mediated endocytosis will be tested. The role of clathrin-coated vesicles in controlling expression of TCR during ontogeny and activation will be defined and the regulatory mechanisms established.
Aim 2 will define mechanisms of class I MHC modulation under normal conditions and during HIV infection. The hypothesis that differential endocytic signals regulate class I MHC expression on the surface of thymocytes, thymic epithelial cells and lymphocytes will be investigated. The effect of expression of the HIV-encoded nef protein in class I MHC expression in these different cell types will be defined and the role of nef in evasion of cytotoxic cell recognition by HIV-infect cells will be analyzed Aim 3 will define mechanisms and immunological consequences of class II MHC modulation during infection by Chlamydia trachomatis. The hypothesis that the reduction in class II MHC expression in Chlamydia-infected cells results from bacteria-induced modification of class II MHC transport through the endocytic pathway will be verified. The mechanism of modification will be defined and T cell stimulation by infected cells will be evaluated as a mechanism for immune evasion by this pathogen.
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