Cis-interaction mediated CD28 costimulation

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Project Summary Engagement of CD28 provides a critical costimulatory signal for T cell activation. Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer and viral infections. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cells protective immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in those T cells is activated in the absence of corresponding ligands on cancer and virus-infected cells, indicating the limited mechanistic understanding of the B7:CD28 pathway. My preliminary data have suggested a novel mechanism of CD28 activation by B7 on the same T cell (cis-B7:CD28 interactions), different from the known CD28 engagement by B7 on antigen-presenting cells (trans-B7:CD28 interactions). This finding has begun to reveal a unique avenue to trigger CD28 signaling in effector T cells for vigorous anti-tumor and ant-virus immune responses. Based on this finding, the objective of this K99/R00 application is to understand the function and mechanism of cis-B7:CD28 interaction and leverage cis-activation of CD28 to enhance the activity of T cells against cancer and infection. To this end, I propose the following aims: Aim 1: Establish a role of B7:CD28 cis- interactions in regulating T cells activity. Aim 2: Dissect the molecular mechanism through which CD28 is activated by B7 ligands in cis. Aim 3: Identify the function of cis-B7:CD28 interaction in T cell immune response against tumor and viral infection. These three aims will allow me to perform a comprehensive investigation on cis-B7:CD28 interactions and the knowledge gained from this study will likely provide valuable therapeutic implications in CD28 targeted T cell therapy. I have a strong background in studying cis-interactions and their functions in regulating T cell activity, which is evidenced by publishing two impactful papers during my postdoctoral training. Importantly, I have established a series of unique and robust approaches to convincingly decouple cis- and trans-interactions in coreceptors signaling. This has been the solid foundation of my proposed experiments. Moreover, my mentorship committee and I have developed an individualized research training and career development plan, which helps me obtain additional skillsets and expertise and ultimately ensures my success in seeking an independent investigator position. University of California, San Diego provides the best possible environment for my K99 research, including world-leading research, cutting-edge facilities and extensive career development resources. Overall, this K99/R00 award will fulfill my career goal to understand the function and mechanism of costimulatory receptor signaling in regulation of T cell activity and promote my career transition into an independent investigator.