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. ? ?
|McCabe, Amanda; Zhang, Yubin; Thai, Vinh et al. (2015) Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection. Stem Cells 33:2294-305|
|Johnson, Theodore S; Terrell, Catherine E; Millen, Scott H et al. (2014) Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol 192:84-91|
|Marsh, Rebecca A; Allen, Carl E; McClain, Kenneth L et al. (2013) Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 60:101-9|
|Terrell, Catherine E; Jordan, Michael B (2013) Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood 121:5184-91|
|Terrell, Catherine E; Jordan, Michael B (2013) Mixed hematopoietic or T-cell chimerism above a minimal threshold restores perforin-dependent immune regulation in perforin-deficient mice. Blood 122:2618-21|
|Risma, Kimberly; Jordan, Michael B (2012) Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 24:9-15|
|Rani, Reena; Jordan, Michael B; Divanovic, Senad et al. (2012) IFN-?-driven IDO production from macrophages protects IL-4R?-deficient mice against lethality during Schistosoma mansoni infection. Am J Pathol 180:2001-8|
|Borges, Margarida; Barreira-Silva, Palmira; Florido, Manuela et al. (2012) Molecular and cellular mechanisms of Mycobacterium avium-induced thymic atrophy. J Immunol 189:3600-8|
|Jordan, Michael B; Allen, Carl E; Weitzman, Sheila et al. (2011) How I treat hemophagocytic lymphohistiocytosis. Blood 118:4041-52|
|Marsh, Rebecca A; Jordan, Michael B; Filipovich, Alexandra H (2011) Reduced-intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward. Br J Haematol 154:556-63|
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