ITAM-Dependent Regulation of MHC Class II Antigen Presentation and CD4+ T cell Priming
Date of Award
Doctor of Philosophy (PhD)
Immunoreceptor tyrosine-based activation motif (ITAM) signaling is a key signaling pathway by which leukocytes sense and respond to environmental cues. Although ITAM signaling has been appreciated for many years in T and B lymphocytes by transmitting downstream signaling of their corresponding immunoreceptors; within the last decade the significance of this pathway in myeloid cell function has come to light. Since then, it has been shown that signaling downstream of a myriad of receptors that associate with the two ITAM containing adaptor proteins DAP12 and FcRgamma; regulates myeloid cell effector function and modulates their responses to extracellular stimuli. Here, we demonstrate that although ITAM signaling can have both activating and inhibitory purposes in myeloid cells, ITAM signaling plays a critical activating role in the promotion of MHC Class II restricted responses both in vitro and in vivo.
In our investigations, we find that in in vitro cultures of bone marrow-derived dendritic cells, ITAM signaling extends the half-life of pMHC Class II complexes by promoting their recycling to the plasma membrane, away from lysosomal degradation, resulting in more efficient MHC Class II antigen presentation. In vivo, ITAM signaling in dendritic cells acts to promote efficient conventional and autoimmune CD4+ T cell priming by regulating dendritic cell migration and antigen presentation. We attribute this in vivo regulation of CD4+ T cell priming to ITAM- dependent migration of dermal dendritic cells and regulation of MHCII antigen presentation in monocyte- derived dendritic cells. Through this work, we elucidate the function of ITAM signaling in MHCII restricted responses, and identify a novel signaling pathway that regulates MHC Class II trafficking.
Chair and Committee
Marina Cella, Marco Colonna, Yina Huang, Robert Schreiber
Akilesh, Holly Marie, "ITAM-Dependent Regulation of MHC Class II Antigen Presentation and CD4+ T cell Priming" (2012). Arts & Sciences Electronic Theses and Dissertations. 56.