This is a revised application for continuation of a grant to study regulation of T cell responses by costimulatory members of the TNFR family. Our continued efforts will examine the role and function of 4-1BB (CD137) in driving the generation and persistence of CD4 and CD8 memory. The hypothesis behind these studies is that 4-1BB signals promote clonal expansion and accumulation of T cells, in part by regulating T cell proliferation and in part by suppressing apoptosis. We will investigate the function of 4-1BB using several in-vivo systems, tracking OT-I CD8 and OT-II CD4 transgenic T cells when 4-1BBL is blocked, and when 4-1BB is absent, using T cells from transgenic mice crossed to 4-1BB-/- mice. We will investigate the contribution of 4-1BB signals to memory generation and longevity under conditions of varying inflammation, including Type 1 and Type 2 cytokine responses. In addition, we will show how 4-1BB/4-1BBL interactions are favored and whether there is differential use by CD4 cells, CD8 cells, or non-T cells. Lastly, memory in secondary lymphoid organs will be compared to peripheral memory responses associated with lung inflammation. ? ? T cell costimulation is becoming an ever increasingly complicated subject with more and more molecules being defined that may positively regulate a T cell. We think this plethora of molecules will ultimately be explained in several ways. One is a quantitative model, in that several molecules will perform the same function at the same time, but with each being absolutely essential to the T cell. Another is a kinetic model, where several molecules will work in a temporal fashion, one after the other, at different times in the lifespan of a responding T cell. Lastly, as antigen-reacting T cells differentiate and become long-lived, their requirements and/or usage of costimulatory molecules will change. This application will aid in delineating the role of one member of the TNFR family in generating and maintaining T cell memory over time. We believe these studies will provide a framework for a model of costimulation that incorporates multiple receptor/ligand interactions. Moreover, it will aid in defining how T cell responses can be effectively targeted for vaccination or therapeutic purposes depending on the type of T cell and the stage in the life of the T cell. ? ?
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