Browsing by Subject "ADAP"
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Item Regulation of autoimmunity and integrin signaling by adaptor proteins ADAP, PRAM-1 and C-CBL(2008-12) Zou, LiangxingTo increase our understanding of adaptor proteins in immune responses, we investigated the roles of adaptor protein ADAP in autoimmune diabetes, and PRAM-1 and c-Cbl in integrin signaling in neutrophils. ADAP deficiency introduced into BDC2.5 transgenic background enhances lymphopenia-stimulated proliferation of autoreactive T cells and autoimmune diabetes, which can be relieved by syngeneic transferred T cells. Further studies suggest that impaired thymic selection, but not defective survival of peripheral T cells, contributes to enhanced lymphopenic stimulation in ADAP-deficient BDC2.5 mice. Therefore, we conclude that ADAP suppresses lymphopenia-dependent autoimmune diabetes through the promotion of thymic output. These data reveal a novel mechanism of autoimmunity regulated by adaptor protein ADAP. When we started to explore the molecular mechanisms regulated by PRAM-1 of integrin signaling in neutrophils, we detected coimmunoprecipitation of c-Cbl and PRAM-1 in NB4 cells. Further, we discovered that c-Cbl positively regulates integrin-dependent oxygen burst but negatively regulates Fc receptor-dependent Ca2+ flux in neutrophils. The underlying molecular mechanisms are currently under investigation. Collectively, data presented in this thesis emphasize the essential roles of adaptor proteins in signal transduction and autoimmunity, and will increase our understanding of adaptor proteins in immune responses.Item Regulation of CD8 T cell memory by ADAP(2014-12) Fiege, JessicaDuring acute infections, naïve antigen-specific CD8 T cells are activated and differentiate into effector T cells, the majority of which undergo contraction after pathogen clearance. A small population of CD8 T cells survives the contraction phase and persists as memory, to protect against future infections. Memory CD8 T cells are heterogeneous and can be found in secondary lymphoid organs (SLOs), blood and non-lymphoid tissues (NLTs). Here I demonstrate the adaptor protein ADAP enhances the formation of memory CD8 T cells in both SLOs and NLTs after pathogen challenge. ADAP-deficient memory CD8 T cells in SLOs proliferate robustly to a systemic secondary challenge. Additionally, ADAP-deficient resident memory CD8 T cells are functional in response to local peptide challenge, but only when in the presence of wild-type antigen-specific T cells. In the absence of an infection, memory-like or memory phenotype (MP) CD8 T cells can arise from homeostatic cytokine exposure during lymphopenia. In contrast to the role of ADAP after pathogen challenge, I have identified a negative regulatory role for ADAP in the formation of MP CD8 T cells in the steady state. Naïve ADAP-deficient CD8 T cells are hyperresponsive to lymphopenia in vivo and exhibit enhanced activation of STAT5 and homeostatic antigen-independent proliferation in vitro in response to IL-15. My results indicate that ADAP dampens naïve CD8 T cell responses to lymphopenia and IL-15, and demonstrates a novel antigen-independent function for ADAP in the suppression of MP CD8 T cell generation. These findings contribute to our knowledge of the generation of different memory CD8 T cell populations, and we hope to augment vaccine efficacy and better understand the formation and maintenance of memory CD8 T cells.