Multiple Pathways of CD28 Costimulation

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DESCRIPTION (provided by applicant): It is well established that costimulation through CD28 can have a dramatic effect on T cell activation, survival, tolerance, and differentiation. However, in spite of considerable interest and effort, it has been unclear whether these different functions of CD28 are all mediated simply through amplification of TCR signaling or through the induction of one or more distinct signaling pathways. We have recently found that CD28 can transduce two independent signaling pathways that result in the upregulation of IL-2 secretion. One pathway is dependent in the ability of CD28 to activate phosphatidylinositol 3-kinase (PI3K) and results in the specific recruitment of PKCtheta to the cSMAC region of the immunological synapse, nuclear translocation of NF-kappaB, and upregulation of IL-2 transcription. This pathway may be mediated through proximal signal integration between TCR and CD28 signaling within the context of specific localization of proteins within the immunological synapse. The second pathway functions in the absence of CD28-mediated activation of PI3K and does not induce recruitment of PKCtheta to the immunological synapse or upregulation of IL-2 transcription. Nevertheless, costimulation through CD28 that cannot activate PI3K still induces normal levels of IL-2 secretion primarily through stabilization of IL-2 mRNA. This pathway also appears to function when CD28 costimulation is provided in trans and so may be mediated by signal integration downstream from the plasma membrane. The overall goal of this proposal is to define the cell biological, biochemical, and molecular steps that mediate these two independent pathways of CD28 costimulation. We will accomplish these goals through two specific aims: 1. Determine how targeting of CD28 and associated signaling molecules to the cSMAC impacts on CD28 costimulation of IL-2 transcription. 2. Identify the components of the PI3-kinase-independent CD28 signaling pathway that lead to IL-2 mRNA stabilization.