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ShcA and Shcbp1 in T Cell Development and Function

Buckley, Monica
Thesis/Dissertation; Online
Buckley, Monica
Ravichandran, Kodi
T cell development and function critically depend upon productive signaling via the pre T cell receptor (preTCR) during early development and the T cell receptor (TCR) at later stages of development and activation. Propagation of signals downstream of the preTCR and TCR requires adapter proteins, including the adapter protein ShcA, to help assemble signaling complexes. Furthermore, I found that ShcA dependent preTCR signaling leads to the upregulation of Shcbp1, a poorly understood protein that binds to the adapter protein ShcA and is elevated in activated lymphocytes. Additionally, Shcbp1 expression tightly correlates with proliferative stages of T cell development. When I generated and analyzed mice deficient in Shcbp1 expression, unexpectedly, loss of Shcbp1 did not have an obvious effect during T cell development in vivo. Shcbp1 is also upregulated in activated T cells and in the context of autoimmunity. I found that in a mouse model of multiple sclerosis, Shcbp1 deficient mice had reduced disease severity and improved survival, and this effect was T cell intrinsic. Thus, Shcbp1 is dispensable for T cell development, but influences CD4+ T cell effector function in autoimmunity. Previously, our laboratory has shown that ShcA is required for progression through the β-selection checkpoint. However, the role of ShcA in signaling via the TCR at the DP stage of development and in late T cell development has not been addressed. I found that ShcA is required for late T cell development and progression from the DP to SP stage of thymocyte development (done in collaboration with Dr. Trampont). Mice expressing a dominant negative ShcA transgene from the DN4/DP stage of development exhibit peripheral lymphopenia and develop attenuated disease in the EAE model of MS. Therefore, ShcA contributes to progression through positive selection checkpoints and the maintenance of peripheral T cell numbers.
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD, 2014
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