The generation of a potent immune response involves not only the primary activation of effector T and B cells but the efficient generation of immune memory. We have observed that congenic mice that differ in Qa-2 subregion gene expression have different immunological phenotypes. The Qua-2- congenic strain B6K1, which has deleted several Qa-2 subregion class Ib genes, fails to generate a IgG2b antibody response following primary immunization with ovalbumin. In addition Qa-2- congenic mice show retarded accumulation of CD4+ T cells bearing memory T cell markers. In contrast, Qa 2+ congenic mice generate a potent IgG2b response to ovalbumin and show normal levels of CD4+ memory T cells. We hypothesize that Qa-2 subregion genes are playing a role in the generation of a potent primary immune response and in the generation of memory T cells.
In Aim #1, we propose to identify the Qa-2 region gene involved by using Qa-2- congenic strains to express various Qa-2 subregion transgenes. Once identified, mutant Qa-2 genes will be used in a attempt to understand how the varied structural features of the molecule are involved in function Aim #2 outlines studies examining the cellular basis for the observed differences. The ability of T cells from Qa-2+ and Qa-2- congenic mice will be examined for their ability to generate antigen-specific CD4_ memory T cells both in vivo and in vitro. Given that cytokines play a key role in controlling IgG production, the ability of CD4+T cells from Qa-2+ and Qa-2- mice to produce cytokines following antigen-specific or mitogen driven stimulation will be examined.
In Aim #3 we will extend these studies to the CD8+ T cell compartment and examine the ability of Qa-2- and Qa-2- and Qa-2- congenic mice to generate a primary and memory CD8+ T cell compartment and examine the ability of Qa-2- and Qa-2- congenic mice to generate a primary and memory CD8+ T cell response to Influenza A. Collectively, these studies are focused on understanding the molecular and cellular basis for the differing immunological capacity of Qa-2+ and Qa-2- congenic mice and the role that Qa-2 subregion gene products play in modulating immune function. Such basic information on genes that effect the generation of effective immunity ar relevant to the design of vaccines. Immunization/vaccination strategies where antigen is co-administered with a reagent binding to a T cell signalling molecule may prove useful in the generation of long term protective immunity. A analogous strategy targeting T cell surface structures involved in co-stimulation has proven to be a effective strategy in the induction of antigen-specific tolerance.
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