All ETDs from UAB

Advisory Committee Chair

Chander Raman

Advisory Committee Members

Patrizia De Sarno

Louis B Justement

John F Kearney

John D Mountz

Alexander J Szalai

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

CD5 has classically been shown to act as a negative regulator of antigen receptor signaling, however recent evidence has discerned that the CD5 molecule contains a previously undefined cytoplasmic domain which constitutively binds inactive CK2 and facilitates its activation through CD5 ligation. With the development of a mouse model which contains a micro-deletion knock-in form of CD5 which lacks the amino acids necessary to facilitate this CD5-CK2 interaction, it is now understood that CD5 plays a more significant role in cellular physiology than previously appreciated. T cells from this mouse model show increased AICD and dysregulation in T helper subset polarization. In mice CD5 expression is limited to only a few different cellular populations, one of which is the innate-like B-1a B cell population. This population has been shown to play a major role in the early natural antibody responses to TI-II antigens, and is a driving force in the clearance of many commonly encountered pathogens. The studies in this dissertation demonstrate a new role for CD5 in B-1a mediated signaling cascades and physiologic responses to T-independent antigens. In these studies we evaluated the impact of the CD5-CK2 signaling domain on shaping the peritoneal cavity cellular distribution and the functional consequences stemming from the loss of this signaling domain on normal B-1a B cells. In addition, by applying what we determined in normal B-1a B cells, we elucidated the role of CD5-CK2 signaling in maintaining B-1a B cell dominated idiotypic responses, specifically with regard to anti-PC responses to S. pneumoniae. Overall, these studies determine a new and previously undefined essential role for the CD5-CK2 signaling axis in maintaining B-1a B cell homeostasis through regulating essential cellular signaling pathways necessary for proliferation, growth, and regulation of immuno-dominant responses.

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