Functional Specialization of Islet Dendritic Cell Subsets

Abstract

Dendritic cells (DC) play important roles in both tolerance and immunity to β-cells in type 1 diabetes. How and why DC can have diverse and opposing functions in islets remains elusive. To answer these questions, islet DC subsets and their specialized functions were characterized. Under both homeostatic and inflammatory conditions, there were two main tissue resident DC subsets in islets, defined as CD11blo/−CD103+CX3CR1− (CD103+DC), the majority of which were derived from Flt3 dependent pre-DC; and CD11b+CD103−CX3CR1+ (CD11b+DC), the majority of which were derived from monocytes. CD103+DC were the major migratory DC and cross-presented islet derived antigen in the pancreatic draining lymph node (LN), although this DC subset displayed limited phagocytic activity. CD11b+DC were numerically the predominant subset (60–80%), but poorly migrated to the draining LN. Although CD11b+ DC had greater phagocytic activity, they poorly presented antigen to T cells. CD11b+DC increased in numbers and percentage during T cell mediated insulitis, suggesting that this subset might be involved in the pathogenesis of diabetes. These data elucidate the phenotype and function of homeostatic and inflammatory islet DC, suggesting differential roles in islet immunity.

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

“…As described in sections 2.1 and 3.1 above, all islets contain intra islet dendritic cells, and these increase as insulitis progresses. Both CD11b ) DCs are present in noninflammed islets, they are more plentiful in the islets of NOD mice, and the CD11b + population expands during insulitis [16,28]. These intra-islet dendritic cells contain beta-cell antigens, including insulin.…”

“…Whilst endothelial cells are deficient in class II molecules, islet DCs (class II+) are intimately associated with the blood vessels. They frequently extend dendrites into the vessel lumen and provide a point of contact for CD4 T cells [28,61]. The efficacy of CD4 T cell localization is further enhanced by interactions with intercellular adhesion molecule 1 (ICAM-1) (Figure 1) [62].…”

“…DCs loaded with beta-cell-derived proteins can be visualized within the PLNs [26]. Two subsets of DCs have been described within islets, the CD11b subset, expresses CCR7, a chemokine receptor associated with DC migration into draining lymph nodes [27,28]. CD103 + DCs were numerically deficient in the PLNs of CCR7 knockout mice, suggesting that CD103 + DC represents the major migratory population derived from islets (Figure 1) [28].…”

“…Two subsets of DCs have been described within islets, the CD11b subset, expresses CCR7, a chemokine receptor associated with DC migration into draining lymph nodes [27,28]. CD103 + DCs were numerically deficient in the PLNs of CCR7 knockout mice, suggesting that CD103 + DC represents the major migratory population derived from islets (Figure 1) [28]. DCs presenting beta-cell proteins to CD4 + T cells in the PLNs have been described as CD11c + CD11b variable [26].…”

“…The detection of cells that express CD11c or F4/80 in T cell-deficient NOD.scid islets has been used to assert that DCs and macrophages infiltrate islets first in the absence of T cells [69]. However, these cells are sparse, and it is now recognized that DCs resident within healthy islets express these same markers [16,28]. Increasing islet infiltration and other changes associated with inflammation result in an increase in DC number, suggesting additional DC infiltration during disease progression [16].…”