In vivo mechanisms of CD8 T cell mediated protective immunity against viral and bacterial infection are incompletely defined. Nevertheless, adoptive transfer of pathogen specific T lymphocytes is under clinical investigation in transplant and HIV infected patients. Our goal is to characterize CD8 T cell mediated immunity in the murine model of Listeria monocytogenes (LM) infection. It is our hypothesis that the ability of CD8 T lymphocytes to confer protective immunity upon transfer into a naive recipient is determined by their antigen specificity and affinity, their activation/effector status, their ability to traffic and their context within the inflammatory response. Our preliminary data show that naive, effector, and memory T cells differ in their ability to repopulate and proliferate in response to infection upon adoptive transfer into naive mice. Furthermore, affinity maturation of the transferred T cell populations appear to increase their protective capacity.
The first aim of this proposal will correlate T cell phenotypes, quantities and affinities with protective immunity. Transferred CD8 and CD4 T lymphocytes will be characterized for in vivo proliferation and trafficking properties.
The second aim i s to determine the impact of antigen specificity upon protective immunity. CD8 T cell lines specific for 7 different LM epitopes have been generated in vitro and will be characterized for their in vivo proliferation and trafficking characteristics. This section will also entail strategies to improve in vitro growth of T lymphocytes.
The third aim i s to dissect the in vivo mechanism of CD8 T cell mediated bacterial clearance. Previous studies have demonstrated that neutrophils are essential mediators of T cell mediated immunity to LM reinfection. We will test the hypothesis that LM specific T cells rapidly recruit neutrophils to sites of LM infection, resulting in bacterial clearance within 24 hours of rechallenge. In summary, the investigations will characterize the relative ability of phenotypically different, antigen specific T cells to mediate protective immunity, determine the impact of different antigen specificities upon protective immunity, and dissect the mechanism of CD8 mediated neutrophil recruitment to sites of bacterial infection. These studies are likely to provide valuable insights with potential implications for adoptive T cell therapy in the treatment of immunodeficiency and malignancy.
| Tuma, Roman A; Giannino, Rielle; Guirnalda, Patrick et al. (2002) Rescue of CD8 T cell-mediated antimicrobial immunity with a nonspecific inflammatory stimulus. J Clin Invest 110:1493-501 |
