A quantitative analysis of T cell responses to stimulatory inputs
Document TypePhD thesis
Access StatusThis item is currently not available from this repository
© 2015 Dr. Julia Mary Marchingo
Upon activation, CD8+ T cells undergo rapid proliferation followed by division cessation and eventual cell death. How T cells integrate a range of alternative signal combinations to make decisions affecting tolerance and response strength still poses a considerable theoretical challenge. In this thesis the number of times a cell divides before reverting to a quiescent state, termed its division destiny, was identified as a key proliferation parameter regulated by multiple T cell stimuli. T cell receptor, costimulation and cytokine signals summed together using a linear addition calculus to regulate division destiny. This simple integration mechanism converted the linear additive components into a geometric increase in peak population expansion. As a consequence the strength of the T cell response was profoundly sensitive to combinations of inputs and could be predicted from the sum of the underlying components. A new method to efficiently measure the regulation of T cell division destiny at a clonal level was developed. Using this method it was demonstrated that the progeny cells of an individual CD8+ T cell clone exhibited highly concordant division destiny outcomes. Furthermore, the linear addition of division destiny observed at the population level also applied at the level of the clonal family tree. The regulation of division destiny by the classic T cell growth factor, interleukin-2 (IL-2), was dissected further. Positive feedback between IL-2 and IL-2 receptor alpha chain (IL-2Rα) expression was examined and the relationship with division destiny found to follow a set of simple deterministic rules. This enabled the onset of T cell division destiny to be predicted from the initial IL-2Rα expression and IL-2 concentration in culture. Collectively, these findings demonstrate that a diverse array of signal inputs following a simple set of quantitative principles can sensitively regulate T cell activation and tolerising decisions to generate complex but predictable response outcomes.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References