Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice

Abstract

Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vβ3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vβ3+ immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vβ3+ T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2g7). Finally, Vβ3+ thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.

Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice

“…Macrophages are not capable of naive T cell priming and most likely have a role in the amplification of autoreactive T cell responses, particularly given their high IL-12 production. One possible interpretation of our findings is that B cells and macrophages possess a functional advantage among NOD professional APC owing to their aberrantly activated state in the periphery (71) and their hyperactivity during maturation (13,14), whereas DC are resting in the steady-state and possess a largely normal ability to activate T cells. Importantly, however, the fact that the presentation of NOD DC defects is context-dependent suggests that the relevance of APC functional defects to autoimmunity will depend upon the maturation signals and the local APC composition.…”

B Cells in Autoimmune Diabetes

“…Unmanipulated NOD mice have a higher frequency of activated B cells compared to non diabetes-prone strains of mice [68]. This was indicated by a higher frequency of CD69 + B220 + B cells in mice as young as 14 days of age.…”

“…This was indicated by a higher frequency of CD69 + B220 + B cells in mice as young as 14 days of age. The CD69 + B cells showed an increase in the level of MHC class II, and the costimulatory molecules B7.1 and B7.2 [68]. It was suggested, by comparison of H-2 g7 -expressing mouse strains with non-H-2 g7 strains that the activated phenotype was correlated with the H-2 haplotype.…”

“…It was suggested, by comparison of H-2 g7 -expressing mouse strains with non-H-2 g7 strains that the activated phenotype was correlated with the H-2 haplotype. This could be related to T cell activation of the B cells following TCR-MHC/Ag interactions [68]. B cells from NOD mice, as well as the H-2 g7 insulitis-prone but diabetesresistant NOR and NOD.B6Idd4B congenic mice, Vol.…”

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

“…Our current findings illustrate that the Glp1r is more widely expressed in immune subpopulations from the NOD, relative to the C57BL/6 background. Chiu et al demonstrated a higher frequency of activated B and T cells in the NOD mouse compared with other strains, including the C57BL/6 mouse [31]. Hence one potential explanation for the differential Glp1r expression could be the activation status of lymphocytes, as we did not discriminate between rested and activated B and T cells during the sorting procedure.…”