: Acute infection of mice with intracellular pathogens such as Vaccinia virus (W) and Listeria monocytogenes (LM) results in potent T cell responses, rapid clearance of the pathogen, and the establishment of long-lived memory. In contrast, Mycobacterium bovis bacillus Calmette-Guerin (BCG) persists in the face of detectable CD4 and CD8 T cell responses, with much less known about their relative size, duration, and ability to generate memory. A key advance in the study of LM and W has been the generation of recombinant pathogens expressing model antigens such as chicken ovalbumin (OVA). Combined with the use of TCR transgenic T cells specific for Class I- and Class II-restricted OVA epitopes, these recombinants have helped facilitate the characterization of in vivo immune responses to acute infection. We propose to: 1) adapt this technology to characterize anti-mycobacterial T cell responses by the creation of a BCG-OVA recombinant; 2) dissect underlying differences of T cell responses in their ability to generate sterilizing, protective immunity to chronically infecting intracellular pathogens such as BCG and acutely infecting pathogens such as LM and W; and 3) assess the activation, expansion, and protective capacity of mycobacteria-specific memory CD4 and/or CD8 T cells following infection. An enhanced understanding of how immune responses to these infections differ will provide insight into the mechanisms governing the generation of optimal CD4 and CD8 T cell responses in vivo.
|Williams, Matthew A; Bevan, Michael J (2005) Cutting edge: a single MHC class Ia is sufficient for CD8 memory T cell differentiation. J Immunol 175:2066-9|
|Williams, Matthew A; Bevan, Michael J (2004) Shortening the infectious period does not alter expansion of CD8 T cells but diminishes their capacity to differentiate into memory cells. J Immunol 173:6694-702|
|Sun, Joseph C; Williams, Matthew A; Bevan, Michael J (2004) CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 5:927-33|