ABSTRACT
A numerical and functional deficiency in invariant NKT (iNKT) cells detectable by 3 wk of age in the thymus and spleen mediates the pathogenesis of type 1 diabetes in NOD mice, but the stage of T cell development at which this deficiency first occurs is unknown. We report in this study that this deficiency develops after the CD4(+)CD8(+) double-positive stage of thymic T cell development and is due to a lineage-specific depletion of CD4(-)CD8(-) double-negative alphabeta T cells and iNKT cells from the thymus between embryonic day 18 and day 1 after birth. Thus, an inheritable defect in a lineage fate decision that elicits a deficiency in fetal thymic iNKT cell development may predispose to susceptibility to type 1 diabetes.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Fetus/immunology , Genetic Predisposition to Disease , Killer Cells, Natural/immunology , T-Lymphocyte Subsets/immunology , Thymus Gland/immunology , Animals , Animals, Newborn , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Lineage/genetics , Cell Lineage/immunology , Diabetes Mellitus, Type 1/genetics , Female , Fetus/pathology , Intracellular Signaling Peptides and Proteins , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Lymphopenia/genetics , Lymphopenia/immunology , Membrane Proteins/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Organ Culture Techniques , Receptors, Antigen, T-Cell, alpha-beta/deficiency , Receptors, Antigen, T-Cell, alpha-beta/genetics , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Thymus Gland/metabolism , Thymus Gland/pathologyABSTRACT
The p75 neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily. p75NTR signaling events have been implicated in both cell cycle arrest and apoptosis depending on which effector molecules are associated with its intracellular domain after ligand binding. Two such effector proteins, p75NTR-associated cell death executor (NADE) and neurotrophin receptor interacting factor (NRIF) promote p75NTR-mediated apoptosis, whereas Schwann cell factor-1 (SC-1) mediates neurotrophin-dependent withdrawal from the cell cycle. An understanding of the expression profiles of these three interacting proteins and p75NTR during embryogenesis is critical for addressing whether these effector proteins might function outside of p75NTR-mediated signaling events. The distribution of NADE, NRIF and SC-1 mRNAs during murine development suggests that the action of these genes is in fact not limited to regions of p75NTR expression. Specifically, a detailed comparison of the spatial and temporal expression domains of NADE, NRIF and SC-1 during brain development revealed regions of co-expression with p75NTR but also illustrates a distinct and discordant spatial and temporal expression. These results yield novel insights into the unique developmental characteristics of the three p75NTR-interacting proteins, thus revealing their diverse signaling potential during embryonic development.
