Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

Abstract

Aims/hypothesis NOD.Igµ null mice lacking mature B cells are highly resistant to diabetes and display poor CD4 T cell responses to autoantigens. Nevertheless, the degree to which different B cell subsets contribute to diabetes in NOD mice remains unresolved. Due to their role in the recognition of microbial and autoantigens, peritoneal B cell characteristics were examined in NOD mice to see if they differ developmentally, phenotypically or functionally in aspects relevant to diabetogenesis. Methods The population dynamics, activation state, migratory behaviour and antigen presentation function were investigated in NOD peritoneal B cells. Results NOD peritoneal B cells were found to express abnormally high levels of co-stimulatory molecules (CD40, CD86 and CD69). In contrast, the expression of L-selectin and integrin α4β1 was markedly reduced in NOD mice compared with BALB/c and C57BL/6 mice. The number of B cells in the peritoneum was lower in NOD than in control mice throughout development; migration of B cells from the peritoneum to the pancreatic lymph nodes in NOD mice was enhanced tenfold. NOD B cells showed no chemotactic response to sphingosine-1-phosphate, which normally acts to retain B cells in the peritoneum. Peritoneal B cells of NOD mice also presented insulin autoantigen to CD4 T cells, inducing T cell proliferation. Conclusions/interpretation NOD peritoneal B cells are hyperactivated, migrate to the pancreatic lymph nodes and are capable of driving insulin-specific CD4 T cell activation. These characteristics could make them important for inducing or amplifying T cell responses against islet-antigens.

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

“…4) [40]. Some of these phenotypes have previously been described for NOD B1a cells and associated with increased activation, migration and capacity for T cell costimulation [41]. Interestingly, alterations in the NOD microflora have been shown to condition some of the surface B1 cell traits [19,20].…”

Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice

“…In SPF NOD mice, a considerable reduction of B1 and B2 type B lymphocyte numbers has been detected [18]. The peritoneal B cells in SPF NOD mice also exhibit an increased activation status, as evidenced by multiple activation markers, including CD40, CD86 and CD69.…”

“…Peritoneal B cells in NOD mice are overactivated and decreased in numbers in the peritoneal cavity [18]. However, in peritoneal B cells from germ-free NOD mice, no such signs of activation were observed.…”

“…This pool of innate-type B cells is regulated by microbial factors and actively participates in the defence against invasion by intestinal microbiota. Recent reports indicate that peritoneal B cells in SPF NOD mice are abnormally activated, but the underlying reason for this remains unclear [18]. Investigation of peritoneal B cells in germ-free NOD mice could clarify whether activation of NOD peritoneal B cells is due to microbial factors or whether it depends on genetic factors that predispose the mice to diabetes.…”

Visualization of Mouse Pancreas Architecture Using MR Microscopy

“…Although lymph nodes have a similar shape, they were ruled out as candidates based on the number and size of these spheres, their microstructural details, and pancreatic structures located nearby. Lymph nodes are fewer in number in the pancreas (three per pancreas) than are islets (Ն500 per pancreas), 6,7 and they tend to be much larger than islets and are generally located along the periphery of the gland (ie, not within the parenchyma) 8,9 (based also on personal communication from Shannon J. Turley and Catharina Alam, authors of Refs. 8 and 9).…”