Hemophagocytic lymphohistiocytosis (HLH) is a childhood disorder of excessive and abnormal immune activation, characterized by severe damage to the bone marrow, and a mortality rate approaching 50%. Nearly all patients with HLH have a severe deficiency of cytotoxic killing by T and NK cells, and many of these patients have been found to harbor mutations in the gene encoding perforin. We developed a novel murine model of this disorder, in which perforin deficient (prf) mice are challenged with lymphocytic choriomeningitis virus (LCMV). Following infection, prf mice develop a phenotype that is nearly identical to HLH. Using this model, we have discovered that the HLH phenotype is directly driven by the abnormal overproduction of interferon gamma (IFN-g) by CD8+ T cells. Additionally, we have found that DC's from prf mice harbor increased amounts of viral antigen and acquire increased capacity to stimulate virus-specific T cells after infection. These findings implicate increased antigen presentation by DC populations as the underlying cause of IFN-g overproduction in prf mice, and suggest that perforin normally functions to down modulate antigen presentation. Multiple cell types that express perforin are known to interact with DC's. In order to identify which of these populations would normally down modulate stimulation by DC's, we have performed a series of cell depletion, transfer, and bone marrow transplantation experiments. These studies have revealed that perforin-expressing cell types can influence both DC function and in vivo IFN-g production, and suggest that CD8+ T cells are the most critical cell type exerting this regulatory effect. Based on our preliminary studies, we hypothesize that perforin-dependant cytotoxic killing of selected dendritic cells by CD8+ T cells limits the entry and/or persistence of antigen in DC populations, and thereby limits immune activation. To test our hypothesis, we will pursue the following specific aims:
Aim 1.) Define how antigen handling and presentation differ between WT and prf DC subsets after LCMV infection.
Aim 2.) Determine whether CD8+ T cells are the principle cell type that suppresses DC stimulatory function via a perforin-dependant mechanism. This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders.
Showing the most recent 10 out of 16 publications
