Medical Biology - Theses
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ItemA quantitative analysis of the PD-1 immune checkpoint in T cell proliferation( 2022)Upon activation, T cells undergo a controlled division burst to form a pool of antigen-specific effector cells. Previous work using quantitative T cell assays has demonstrated that parameters including entry into division, subsequent division rate, cell survival, and the number of times the cells divide before returning to quiescence (termed division destiny) determine the size and duration of the division burst. These key variables are independently controlled by the type and strength of T cell receptor (TCR), co-stimulatory and cytokine signals received during activation. Marchingo et al. (2014) established that co-stimulatory inputs linearly sum to determine division destiny and consequently the overall size of the response. I investigated how inhibitory signals integrate into this linear addition model of multiple co-stimulatory signals. Co-inhibitory receptors, such as programmed death receptor 1 (PD-1) are expressed on T cells after activation and are known to inhibit T cell responses. I focused on PD-1 as a quintessential inhibitory signal that has been well established as a cell intrinsic inhibitory signal in T cells. However, the precise mechanisms by which PD-1 modulates T cell proliferative responses are not yet fully understood. Thus, I applied a quantitative approach to investigate the role of PD-1 signalling in CD8+ T cell proliferative responses. I developed a quantitative dendritic cell-T cell co-culture assay for controlled delivery of co-stimulatory and inhibitory signals, including PD-1, to T cells in vitro. Using this system, I discovered that PD-1 signalling reduced proliferation of naive T cells by specifically decreasing division destiny, with no effect on cell survival. Moreover, I uncovered a novel IL-2-independent pathway for PD-1-mediated inhibition, yet IL-2 signalling also amplifies the inhibitory effect of PD-1. I go on to show that PD-1 reduces division destiny independent of TCR, CD28 signals and 4-1BB signals. From these findings I propose that PD-1 integrates with the calculus of multiple co-stimulatory signals by linearly subtracting from division destiny to influence the overall magnitude of the proliferative response.