The Role of the ERK-MAPK Pathway and Stathmin in T Cell Development and Activation

T lymphocytes are integral cells of the adaptive immune system. They respond to a wide variety of pathogens to induce humoral immunity, kill infected host cells and provide long-lasting memory for the host organism. The development and activation of T cells has been well studied, however, numerous questions remain about the details of these processes. The ERK-MAPK pathway is a signaling cascade that has been shown to play a critical role in T lymphocyte development and function. Aside from the core kinase components (Raf/MEK/ERK), numerous proteins exist to modulate the MAPK pathway, influencing the duration and localization of signaling. The first part of this thesis focuses on the role of the MAPK scaffold protein Kinase Suppressor of Ras 1 (KSR1) in thymocyte development. It was previously shown that KSR1 is required for ERK activation at the immune synapse. Here we show that lack of KSR1 in thymocyes leads to a significant inhibition of ERK activation. Surprisingly, however, thymocyte development in three different mouse models proceeded normally despite minimal activation of ERK. This finding suggests the role of ERK in thymocyte selection should be re-evaluated, particularly data implicating strength and duration of ERK signaling in positive selection. The second part of this work focuses on cytosolic targets of ERK that might mediate its effect on peripheral T cell functions, including migration and cytolysis. We identify stathmin as an ERK-regulated protein that is phosphorylated by membrane associated ERK at the immune synapse during T cell activation. Depletion of stathmin by gene knockout in mice results in a phenotype in which microtubule dynamics are altered and MTOC polarization is defective to anti-CD3 coverslips. Stathmin-knockout T cells can form synapses, migrate and proliferate normally. However, CD8 T cells from stathmin knockout mice cannot kill as well as those from wild type. This suggests that stathmin plays a role in regulating microtubule dynamics and select microtubule-dependent functions of activated T cells