This proposal will examine the interplay of TCR avidity with other biological properties of CD8+ cytotoxic Tlymphocites (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 - naive, 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 CDS response to a single, exquisitely immunodominant peptide (glycoprotein 8495.502, 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 naive, effector and memory T-cell subsets?:
and Aim 2 What is the role of variation in individual CTL properties 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 way for manipulation of its efficacy in infectious diseases in general as well as in specific protection against ocular and CMS manifestations of the corneal HSV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066096-03
Application #
7204226
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Beisel, Christopher E
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$364,753
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Rudd, Brian D; Venturi, Vanessa; Smith, Norah L et al. (2013) Acute neonatal infections 'lock-in' a suboptimal CD8+ T cell repertoire with impaired recall responses. PLoS Pathog 9:e1003572
Rudd, Brian D; Venturi, Vanessa; Li, Gang et al. (2011) Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc Natl Acad Sci U S A 108:13694-9
Rudd, Brian D; Venturi, Vanessa; Davenport, Miles P et al. (2011) Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J Immunol 186:2056-2064
Rudd, Brian D; Venturi, Vanessa; Smithey, Megan J et al. (2010) Diversity of the CD8+ T cell repertoire elicited against an immunodominant epitope does not depend on the context of infection. J Immunol 184:2958-2965
Messaoudi, Ilhem; Barron, Alexander; Wellish, Mary et al. (2009) Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans. PLoS Pathog 5:e1000657
Rudd, Brian D; Brien, James D; Davenport, Miles P et al. (2008) Cutting edge: TLR ligands increase TCR triggering by slowing peptide-MHC class I decay rates. J Immunol 181:5199-203
Braaten, Douglas C; McClellan, James Scott; Messaoudi, Ilhem et al. (2006) Effective control of chronic gamma-herpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells. PLoS Pathog 2:e37