Signaling of the T Cell Costimulatory Receptor CD28: Regulation and Initiation

Abstract

T cells provide antigen-specific immunity to pathogens, but are also capable of inducing destructive autoimmunity when responding to self antigens. In order to achieve full activation, T cells must receive two signals: one from the T cell antigen receptor, and a second from a costimulatory receptor, such as CD28. Expression of the ligands for CD28 activation is strongly induced on professional antigen presenting cells under conditions of inflammation or danger-sensing. Hence, CD28 costimulatory receptor acts as a gatekeeper to T cell activation and is essential in maintaining the balance between immunity and self-tolerance. CD28 function has been implicated in many animal models of T cell-dependent infection control and autoimmune disorders. Intensive study of CD28 signaling biology over more than two decades has elucidated key signaling pathways and transcriptional targets that help to explain the unique CD28-dependent functions in T cells. Some signaling pathways downstream of CD28 activation have been mapped to particular motifs within the CD28 cytoplasmic domain, although no consensus has emerged on the importance of these signaling motifs to CD28 function in vivo. This thesis describes the discovery of a novel motif within CD28 cytoplasmic domain that regulates receptor signal initiation through membrane binding and kinase recruitment, and discusses the new findings in light of existing literature.