CD1d is a major histocompatibility complex (MHC) class 1-related molecule that is expressed by intestinal epithelial cells (lEC), hepatocytes and professional antigen presenting cells (APCs) including dendritic cells (DC), monocytes and B cells. CD1d functions in the presentation of the host and microbialy derived lipid antigens to CD1d-restricted T cells that express natural killer (NK) and T cell markers (sd-called NKT cells). CD1d-restricted antigen presentation is operational during the earliest phases of an immune response, which, together with the broad array of cytokines secreted by activated NKT cells, accounts for the wide range of effects that CD1d-restricted presentation has on immune-mediated processes in vivo. Although the cell biology of the host (and microbial) lipid antigen acquisition by CD1d or the role of CD1d-restricted Antigen presentation pathways in mucosal tissues is poorly understood, CD1d-restricted pathways; are now| known to regulate inflammation and host defense in the intestines and liver. We propose to examine the recently appreciated relationship between microsomal triglyceride transfer protein (MTP), an endoplaismic reticulum (ER) resident protein, which possesses a well-known role in lipid absorption mediated through the lipidation of apolipoprotein-B in the liver and intestine, and the immune functions of CD1d.
Aim 1 investigates the hypothesis that MTP is responsible for the lipidation and assembly of CD1d and seeks; to prove that MTP lipidates CD1d, to define the location within CDId biogenesis that MTP functions relative to other ER chaperones, to determine whether MTP has distinct lipidation and chaperone functions for CD1d and to define the cellular locale of CD1d when MTP is absent.
Aim 2 proposes to determine whether MTP is expressed by and is functional in professional APCs such as DCs and B cells, to determine whether:MTP affects CD1d trafficking behavior in professional APCs and establish an in vivo model for MTP deficiency in hemotopoietic cells.
Aim 3 proposes to use mice with conditional deletion of MTP in lECs to define the role of these pathways in the development of colitis due abnormal barrier function and the specific role that the lEC and CD1d restricted antigen presentation plays in the development of colitis.
Aim 4 proposes to define the role of CD1d in regulating intestinal colonization with commensal bacteria and determine if MTP ; regulates bacterial colonization of the intestine and define the APC involved
Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident protein that has recently been appreciated to provide the nascent lipid(s) for CD1 assembly during its biogenesjs in addition to its previously recognized role in lipid absorption during digestion. Given the role of CD1d in participating in a wide variety of immune-mediated diseases, understanding the mechanisms of MTP-mediated lipidation of CD1 and its functional consequences is extremely important. Such studies will form the basis for the possibility of specifically inhibiting CD1 at its earliest stages of assembly within the SR and thus provide opportunities for controlling inappropriate inflammatory responses or enabling others that may normally be inhibited by CD1-mediated pathways.
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