Acquired immunity to intracellular pathogens depends on T cell recognition of HLA-bound microbial peptides. Pathogens that occupy phagosomes are controlled by CD4+ cells that recognized microbial peptides bound to HLA class II. While these interactions occur in response to Mycobacterium tuberculosis, they are only partially efficacious: the human immune system is unable to completely resolve infection with M. tuberculosis. M. tuberculosis has been found to inhibit class II antigen presentation, but the mechanisms has not been determined. The goal of this project is to define the mechanism of inhibition of class II antigen present in human macrophages infected with M. tuberculosis. We have found that M. tuberculosis causes a decrease of cell surface class II (HLA-DR) in macrophages, without a decreased in the total cellular HLA-DR pool. This suggests that M. tuberculosis alters trafficking of class II. We will further characterize the decreased surface expression of class II by determining whether it is directly related to the number of intracellular M. tuberculosis and by comparing expression of HLA-DR on infected macrophages and dendritic cells. We will test the hypothesis that HLA-DR is sequestered in M. tuberculosis phagosomes, and will determine whether HLA-DR is sequestered due to failure of exchange of exogenous peptides for CLIP. We will also further characterize the functional effects of M. tuberculosis down-regulation of HLA-DR. We will determine whether down-regulation of class II inhibits CD4+ cell recognition of extracellularly loaded M. tuberculosis antigens and whether M. tuberculosis antigens and whether M. tuberculosis inhibits allogeneic responses. Finally, we will test the hypothesis that inhibition of class II antigen presentation is an inherent property of mycobacteria by comparing the response of CD4+ T cell lines that recognize a DR3-restricted epitope of M. tuberculosis hsp65 when it is expressed by mycobacteria or by an alternative vehicle. We anticipate that our results will provide new information on the pathogenesis of tuberculosis, and may identify alternative means of delivering M. tuberculosis antigens for vaccination.
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