In this application, I propose to analyze virus-specific CD4+T cells in two animal models of virus infection, selected because they represent the two ends of the immunological spectrum; one induces strong CD8 + T cell responses [lymphocytic choriomeningitis virus (LCMV)], while the other induces strong CD4 + T cell/antibody responses [coxsackievirus B3 (CVB3)]. We have two general goals: first, to measure CD4 + T cell function at the cellular and organismal levels (Aims 1 & 2 respectively); and, second, to identify the factors which appear to restrict the expansion of antigen-specific CD4 + T cells (Aim 3). All of our analyses will be done using normal T cells, evaluated directly ex vivo.
Aim 1 : We shall examine the antigen-responsiveness of primary and memory CD4 + T cells, and determine whether or not they undergo functional avidity maturation during the course of viral infection.
Aim 2 : We shall investigate the role of vaccine-induced CD4 + T cells in modifying the immune responses to subsequent viral infection; and we will measure the protective benefits of these cells. These experiments will exploit our experience with LCMV (a virus controlled by CD8 + T cells) and with CVB3 (which is controlled by antibodies). We shall generate a stable of recombinant CVB expressing a variety of CD8 and CD4 epitopes.
Aim 3. Immunodominance is an important immunological phenomenon which profoundly affects CD8 + T cell responses. Our preliminary data indicate that it also affects CD4 + T cell responses; and that CD8 + T cells actively suppress CD4 + T cell expansion. This may explain why, during LCMV infection, CD8 + cells greatly outnumber CD4 + cells. We shall investigate this further, and will determine the underlying mechanism. This may allow us to circumvent the problem, thus permitting the design of vaccines which could induce elevated levels of CD4 + T cell memory.
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