TRAF3 regulates B cell survival and IL-6 receptor signaling

has been approved by the Examining Committee for the thesis requirement for the Doctor of Philosophy degree in Immunology at the May 2015 graduation. ii To my family and friends, thank you for the endless support iii ACKNOWLEDGEMENTS First and foremost, I would like to thank my mentor, Dr. Gail Bishop, for her mentorship and support for the past five years. Gail provided me with excellent guidance and encouragement throughout my graduate training. Her endless support has not only fostered me to become a better scientist but also to become a better writer, and speaker. Without her support and guidance, my thesis work would not have been accomplished. I would like to thank the Interdisciplinary Graduate Program in Immunology for providing an excellent learning and training environment, and Dr. Bishop and Dr. Varga for overseeing the program. Special thanks go to Paulette Villhauer, Joshua Lobb and Kathy Dautremont for keeping me in check with the paperwork and deadlines. I would especially like to thank my thesis committee members (Dr. Quelle) for their guidance and support for my thesis work. I also wish to thank the Biosciences Program for providing me with financial support during my initial year of graduate school. I also would like to express my gratitude to the past and current Bishop lab members for providing me with technical expertise, insightful advice, and friendship during the past five years. I especially thank Dr. who played very significant roles during my graduate training. I also acknowledge Dr. Bruce Hostager for constructive scientific discussions and critical reviews of my manuscripts. Lastly, I thank my family and friends. Without their support, I would not have accomplished my graduate school goal. iv ABSTRACT Tumor-necrosis factor (TNF)-receptor (R) associated factor 3 (TRAF3) is an important adaptor protein that plays a variety of context-dependent regulatory roles in all types of immune cells. In B cells, TRAF3 mediates signaling downstream of CD40, B cell activating factor (BAFF)-R, and toll-like receptors (TLR)s to restrain B cell survival and function. Downstream of CD40 and BAFF-R, TRAF3 negatively regulates NF-κB2 activation through NF-κB inducing kinase (NIK) stabilization. NF-κB2 activation is important for B cell-homeostatic survival. However, the constitutively active NF-κB2 in other TRAF3 deficient immune cell types does not lead to increased cell survival. More importantly, loss-of-function mutations of the TRAF3 gene are found at relatively high frequencies in B cell malignancies such as multiple myeloma and B …