» Articles » PMID: 8450229

Defects in the Differentiation and Function of Antigen Presenting Cells in NOD/Lt Mice

Overview
Journal J Immunol
Date 1993 Mar 15
PMID 8450229
Citations 76
Authors
Affiliations
Soon will be listed here.
Abstract

Although T lymphocytes are the ultimate effectors of pancreatic beta cell destruction in autoimmune insulin-dependent diabetes, previous work has established that beta cell autoreactive T cells are generated in nonobese diabetic (NOD) mice as a result of APC dysfunctions. To determine if APC dysfunctions could result from developmental defects, we analyzed if macrophages (M phi) develop normally from NOD bone marrow stimulated with CSF-1 in the presence and absence of IFN-gamma. Due to interactions between the diabetogenic H-2g7 haplotype and background modifiers, NOD bone marrow cells were found to proliferate poorly to CSF-1 stimulation. IFN-gamma aberrantly increased CSF-1-stimulated proliferation of H-2g7 expressing bone marrow cells, although decreasing proliferation of bone marrow cells expressing diabetes resistant MHC haplotypes. FACS analysis indicated the diminished sensitivity of NOD hematopoietic precursors to CSF-1 was associated with a quantitative inability to generate phenotypically mature M phi. In addition to developmental defects, NOD M phi were also found to be functionally defective. Total MHC class I expression was aberrantly down-regulated in a tissue specific fashion in IFN-gamma-treated M phi from NOD mice, whereas MHC class I expression increased as expected in M phi from C57BL/KsJ (BKs) control mice. Total MHC class I expression also increased in IFN-gamma-treated M phi from NOR mice, a diabetes-resistant control strain that shares the H-2g7 haplotype of NOD, but contains BKs-derived genomic elements on chromosomes 2, 4, 11, and 12. This demonstrates differential trans-regulation of class I loci within the diabetogenic H-2g7 haplotype in NOD vs diabetes-resistant NOR mice. Aberrant down-regulation of MHC class I content in IFN-gamma-treated M phi from NOD mice was associated with decreased ability to activate CTL function. We propose these defects in M phi differentiation and function may interact with H-2g7 to generate APC in NOD mice that are unable to activate tolerogenic mechanisms, but remain capable of activating low level effector responses.

Citing Articles

In-depth cross-validation of human and mouse CD4-specific minibodies for noninvasive PET imaging of CD4 cells and response prediction to cancer immunotherapy.

Pezzana S, Blaess S, Kortendieck J, Hemmer N, Tako B, Pietura C Theranostics. 2024; 14(12):4582-4597.

PMID: 39239511 PMC: 11373626. DOI: 10.7150/thno.95173.


Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans.

Skelly D, Graham J, Cheng M, Furuta M, Walter A, Stoklasek T bioRxiv. 2024; .

PMID: 39071392 PMC: 11275897. DOI: 10.1101/2024.07.11.603136.


A Monocytic Barrier to the Humanization of Immunodeficient Mice.

Du E, Muench M Curr Stem Cell Res Ther. 2023; 19(7):959-980.

PMID: 37859310 PMC: 10997744. DOI: 10.2174/011574888X263597231001164351.


A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice.

Hess J, Eberhard M, Segura-Lepe M, Grundner-Culemann K, Kracher B, Shryock J Sci Rep. 2023; 13(1):976.

PMID: 36653420 PMC: 9849205. DOI: 10.1038/s41598-023-27537-z.


Fluorine MR Imaging Probes Dynamic Migratory Profiles of Perfluorocarbon-Loaded Dendritic Cells After Streptozotocin-Induced Inflammation.

Saini S, Vanherwegen A, Liang S, Verbeke R, Korf H, Lentacker I Mol Imaging Biol. 2022; 24(2):321-332.

PMID: 35060024 DOI: 10.1007/s11307-021-01701-1.