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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DK044319-13
Application #
6924283
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
1992-09-30
Project End
2010-04-30
Budget Start
2005-05-15
Budget End
2006-04-30
Support Year
13
Fiscal Year
2005
Total Cost
$675,210
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit et al. (2018) Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell 173:1123-1134.e11
Aden, Konrad; Tran, Florian; Ito, Go et al. (2018) ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J Exp Med 215:2868-2886
Gensollen, Thomas; Blumberg, Richard S (2017) Correlation between early-life regulation of the immune system by microbiota and allergy development. J Allergy Clin Immunol 139:1084-1091
Tschurtschenthaler, Markus; Adolph, Timon E; Ashcroft, Jonathan W et al. (2017) Defective ATG16L1-mediated removal of IRE1? drives Crohn's disease-like ileitis. J Exp Med 214:401-422
Zeissig, Sebastian; Peuker, Kenneth; Iyer, Shankar et al. (2017) CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc Natl Acad Sci U S A 114:10449-10454
Hosomi, Shuhei; Grootjans, Joep; Tschurtschenthaler, Markus et al. (2017) Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J Exp Med 214:2985-2997
Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J et al. (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16:469-84
Gensollen, Thomas; Iyer, Shankar S; Kasper, Dennis L et al. (2016) How colonization by microbiota in early life shapes the immune system. Science 352:539-44
Peuker, Kenneth; Muff, Stefanie; Wang, Jun et al. (2016) Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat Med 22:506-15
Nakanishi, Yuki; Reina-Campos, Miguel; Nakanishi, Naoko et al. (2016) Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKC?/?. Cell Rep 16:3297-3310

Showing the most recent 10 out of 80 publications