This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This proposal will examine the interplay of TCR avidity with other biological properties of CD8+ cytotoxic T-lymphocytes (CTL) that may be important in immune defense - migration, proliferation and acquisition of different effector functions. In principle, these properties may be independent of each other (stochastic diversification). Alternatively, they could be orchestrated by one property (e.g., TCR avidity and/or differentiation status of the cell na ve, effector or memory). Experiments proposed here will evaluate which of the CTL properties may be critically important for immune defense in vivo, and whether and to what extent these properties may be coordinated in their expression. These issues will be examined in a model of corneal infection with the Herpes simplex virus 1 (HSV-1). This infection is amongst the leading causes of pathogen-caused blindness in the industrial world. In both the experimental animals and in humans, ocular entry leads to viral spread to the brain, where the CD8+ cytotoxic T lymphocytes (CTL) are critical for viral clearance and survival. In addition to being a good model of human infection, corneal HSV in C57BL/6 mice brings four unique advantages: (i) ability to focus the CD8+ response to a single, exquisitely immunodominant peptide (glycoprotein B495-502, gB-8p); (ii) availability of coisogenic mouse strains which exhibit wide variations in TCR avidity for gB-8p:MHC; (iii) availability of sophisticated tools (TCR transgenic lines, tetrameric reagents, Ag-specific clones); and (iv) recent elucidation by this laboratory of the kinetics of viral spread and of the CTL activation, migration and function in various organs following corneal HSV-1 infection.
The aims will ask:
Aim 1. Is the variation in CTL migration, proliferation and function influenced by TCR avidity in na ve, effector and memory T-cell subsets?Aim 2 What is the role of variation in individual CTL properties avidity, migration, proliferation and function in immune defense against HSV-1 in vivo? These studies should provide novel insights into the fundamental biology of an efficient CTL response in vivo, and pave the way for manipulation of its efficacy in infectious diseases in general as well as in specific protection against ocular and CNS manifestations of the corneal HSV infection.
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