CD1d is a major histocompatibility complex (MHC) class l-related molecule that is expressed by intestinal epithelial cells (lECs), hepatocytes and professional antigen presenting cells (APCs) including dendritic cells (DC), monocytes and B cells. CD1d functions in the presentation of host glycolipid antigens to CDId-restricted T cells that express natural killer (NK) and T cell markers (so-called NKT cells). CDId-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 affects that CDId-restricted antigen presentation has on immune-mediated processes in vivo. Although the cell biology of host glycolipid antigen acquisition by CD1d or the role of CDId-restricted antigen presentation pathways in mucosal tissues is poorly understood, CDId-restricted pathways are now known to regulate intestinal inflammation and mucosal host defense. We now propose to examine the recently appreciated relationship between microsomal triglyceride transfer protein (MTP), an endoplasmic 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 CD1d 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 hematopoietic cells.
Aim 3 proposes to use conditional knockout animal models of MTP to define the role of MTP in the development of colitis due to abnormal barrier function and the specific role of the IEC, to define the role of MTP in the development of colitis due to excess effector cell responses and the specific role of the hematopoietic cells and to determine if MTP has a role in affecting regulatory pathways 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.
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