Increased Generation of Dendritic Cells from Myeloid Progenitors in Autoimmune-Prone Nonobese Diabetic Mice

Abstract

Aberrant dendritic cell (DC) development and function may contribute to autoimmune disease susceptibility. To address this hypothesis at the level of myeloid lineage-derived DC we compared the development of DC from bone marrow progenitors in vitro and DC populations in vivo in autoimmune diabetes-prone nonobese diabetic (NOD) mice, recombinant congenic nonobese diabetes-resistant (NOR) mice, and unrelated BALB/c and C57BL/6 (BL/6) mice. In GM-CSF/IL-4-supplemented bone marrow cultures, DC developed in significantly greater numbers from NOD than from NOR, BALB/c, and BL/6 mice. Likewise, DC developed in greater numbers from sorted (lineage−IL-7Rα−SCA-1−c-kit+) NOD myeloid progenitors in either GM-CSF/IL-4 or GM-CSF/stem cell factor (SCF)/TNF-α. [3H]TdR incorporation indicated that the increased generation of NOD DC was due to higher levels of myeloid progenitor proliferation. Generation of DC with the early-acting hematopoietic growth factor, flt3 ligand, revealed that while the increased DC-generative capacity of myeloid-committed progenitors was restricted to NOD cells, early lineage-uncommitted progenitors from both NOD and NOR had increased DC-generative capacity relative to BALB/c and BL/6. Consistent with these findings, NOD and NOR mice had increased numbers of DC in blood and thymus and NOD had an increased proportion of the putative myeloid DC (CD11c+CD11b+) subset within spleen. These findings demonstrate that diabetes-prone NOD mice exhibit a myeloid lineage-specific increase in DC generative capacity relative to diabetes-resistant recombinant congenic NOR mice. We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice.

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

“…These overall results using pools of adherent and nonadherent cells suggest that both NOD and (NOD ϫ C57BL/6)F 1 dendritic cells fail to mature and are consistent with several previous analyses of NOD dendritic cells (12,(43)(44)(45)(46). However, others have reported that the abnormality of NOD dendritic cells is not immaturity but rather hyperactivation (47,48). These discrepancies could be related both to the developing autoimmune state in the NOD mouse and/or to the particular subpopulation of cultured cells that was analyzed.…”

Bone Marrow Precursors of Nonobese Diabetic Mice Develop into Defective Macrophage-Like Dendritic Cells In Vitro

“…An important difference between our current investigation and previous studies, in which an increased generation or enhanced stimulatory capacity of DC generated from NOD BM have been reported (15,16), is that we did not use IL-4 in our culture system. A supportive effect of IL-4, added to GM-CSF, for the generation and maturation of NOD BM-derived DC was observed in several studies before (13,14,41,42).…”

“…In marked contrast to the reports on ex vivo DC isolated from prediabetic NOD mice, in vitro studies show significant abnormalities in DC yield and development when NOD DC are generated from bone marrow (BM) precursors (12)(13)(14)(15)(16). Studies where NOD BM precursors are stimulated with GM-CSF alone show generation of low numbers of DC that display an immature phenotype and a poor T cell-stimulatory capacity (13,14,17).…”

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

“…Also, another study found an increased proportion of the CD11b C CD11c C DC subset within spleen in NOD, but not in congenic non-obese diabetes-resistant (NOR) mice, compared with BALB/c and C57BL/6 mice. 35 This was further reinforced by data showing increased percentage of CD11b C DCs during insulitis. Thus, the phenotype of the CD11b C DCs associated with late diabetes onset needs further investigation.…”