Impact of T cell - dendritic cell interactions on the clearance of a persistent viral infection
Final Report Abstract
The goal of anti-viral therapy is to promote pathogen clearance without causing tissue injury. Therapeutic administration of anti-viral T cells (adoptive immunotherapy) has shown promise in clinical studies for the treatment of CMV, EBV, and adenovirus. Our laboratory models adoptive immunotherapy by transferring anti-viral memory T cells into mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV). Here we demonstrate that brain-resident myeloid cells (microglia), in addition to neurons, are persistently infected with LCMV in carrier mice. Therapeutic memory T cells can enter the persistently infected CNS without injuring the blood brain barrier or causing parenchymal pathology. This is accomplished through a tailored release of chemoattractants that recruit adaptive immune cells, but few pathogenic innate immune cells. In addition, adoptive immunotherapy induces expression of CD11c and MHC II on most microglia, suggesting conversion into a professional antigen presenting cell. We observed similarly converted myeloid cells in the brains of humans infected with JC virus and HIV-1. Using two-photon microscopy, we revealed that during clearance of the LCMV-infected brain anti-viral CD8 T cells form stable, non-cytopathic interactions with CD11c+ microglia, whereas CD4 T cells interact transiently. We propose that noncytopathic viral clearance from the brain by therapeutic memory T cells results from tailored chemoattractant production and brain-resident APCs that resist the cytopathic effector mechanisms used by anti-viral T cells while still allowing viral clearance.
Publications
- Migration of cytotoxic lymphocytes in cell cycle permits local MHC I-dependent control of division at sites of viral infection. J Exp Med. 2011 Apr 11;208(4):747-59
Kang SS, Herz J, Kim JV, Nayak D, Stewart-Hutchinson P, Dustin ML, McGavern DB
- Two-photon imaging of microbial immunity in living tissues. Microscopy and Microanalysis. 2012 Aug:18(4):730- 41
Herz J, Zinselmeyer BH, McGavern DB
- Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. Immunity. 2013 Mar 21;38(3):502-13
Kastenmüller W, Brandes M, Wang Z, Herz J, Egen JG, Germain RN
