Although T lymphocytes are the ultimate effectors of pancreatic β cell destruction in autoimmune insulin-dependent diabetes, previous work has established that β 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∅) develop normally from NOD bone marrow stimulated with CSF- 1 in the presence and absence of IFN-γ. Due to interactions between the diabetogenic H-2(g7) haplotype and background modifiers, NOD bone marrow cells were found to proliferate poorly to CSF-1 stimulation. IFN-γ aberrantly increased CSF-1-stimulated proliferation of H-2(g7) 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∅. In addition to developmental defects, NOD M∅ were also found to be functionally defective. Total MHC class I expression was aberrantly down- regulated in a tissue specific fashion in IFN-γ-treated M∅ from NOD mice, whereas MHC class I expression increased as expected in M∅ from C57BL/KsJ (BKs) control mice. Total MHC class I expression also increased in IFN-γ- treated M∅ from NOR mice, a diabetes-resistant control strain that shares the H-2(g7) 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-2(g7) haplotype in NOD vs diabetes- resistant NOR mice. Aberrant down-regulation of MHC class I content in IFN- γ-treated M∅ from NOD mice was associated with decreased ability to activate CTL function. We propose these defects in M∅ differentiation and function may interact with H-2(g7) to generate APC in NOD mice that are unable to activate tolerogenic mechanisms, but remain capable of activating low level effector responses.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Immunology|
|State||Published - Jan 1 1993|
ASJC Scopus subject areas
- Immunology and Allergy