Defects in the differentiation and function of antigen presenting cells in NOD/Lt Mice

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 (MØ) 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 MØ. In addition to developmental defects, NOD MØ 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 MØ from NOD mice, whereas MHC class I expression increased as expected in MØ from C57BL/KsJ (BKs) control mice. Total MHC class I expression also increased in IFN-γ-treated MØ 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 frans-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 MØ from NOD mice was associated with decreased ability to activate CTL function. We propose these defects in MØ differentiation and function may interact with H-2^g7 to generate ARC in NOD mice that are unable to activate tolerogenic mechanisms, but remain capable of activating low level effector responses.