I-Ag7-Mediated Antigen Presentation by B Lymphocytes Is Critical in Overcoming a Checkpoint in T Cell Tolerance to Islet β Cells of Nonobese Diabetic Mice

Abstract

B cell-deficient nonobese diabetic (NOD) mice are protected from the development of spontaneous autoimmune diabetes, suggesting a requisite role for Ag presentation by B lymphocytes for the activation of a diabetogenic T cell repertoire. This study specifically examines the importance of B cell-mediated MHC class II Ag presentation as a regulator of peripheral T cell tolerance to islet β cells. We describe the construction of NOD mice with an I-Ag7 deficiency confined to the B cell compartment. Analysis of these mice, termed NOD BCIID, revealed the presence of functionally competent non-B cell APCs (macrophages/dendritic cells) with normal I-Ag7 expression and capable of activating Ag-reactive T cells. In addition, the secondary lymphoid organs of these mice harbored phenotypically normal CD4+ and CD8+ T cell compartments. Interestingly, whereas control NOD mice harboring I-Ag7-sufficient B cells developed diabetes spontaneously, NOD BCIID mice were resistant to the development of autoimmune diabetes. Despite their diabetes resistance, histologic examination of pancreata from NOD BCIID mice revealed foci of noninvasive peri-insulitis that could be intentionally converted into a destructive process upon treatment with cyclophosphamide. We conclude that I-Ag7-mediated Ag presentation by B cells serves to overcome a checkpoint in T cell tolerance to islet β cells after their initial targeting has occurred. Overall, this work indicates that the full expression of the autoimmune potential of anti-islet T cells in NOD mice is intimately regulated by B cell-mediated MHC class II Ag presentation.

Productive Germinal Center Responses Depend on the Nature of Stimuli Received by Anti-Insulin B Cells in Type 1 Diabetes–Prone Mice

“…These data also show that accelerated T1D development can occur even when limited anti-insulin IgG is present, due to IgM isotype restriction by this non-site-directed/class-switch-incompetent V H 125Tg ( 7 , 14 , 15 ). The finding that anti-insulin B cells can present autoantigen to T cells in vitro and support an Ab-independent role in driving T1D development ( 7 ) is consistent with studies showing that B cell–specific deletion of the diabetogenic MHC class II molecule, IA g7 , is also disease protective in NOD mice ( 8 ).…”

Factors Governing B Cell Recognition of Autoantigen and Function in Type 1 Diabetes

“…T1D susceptibility and GAD-specific T cell responses were restored in NOD.Igμ mice reconstituted with syngeneic bone marrow and NOD B lymphocytes but not those with syngeneic bone marrow only [ 7 ]. NOD mice with B cell-specific deficiency in MHC class II molecule I-Ag7 are protected from T1D [ 33 ]. B-cell-depleted CD4+ NOD T cells were unable to divide in response to soluble anti-CD3 and anti-CD28 stimulation, in contrast to B6 CD4+ T cells, which underwent successive rounds of division during the culture period.…”

CD22L Conjugation to Insulin Attenuates Insulin-Specific B Cell Activation

“…Prior tolerization studies with BCR–CD22 colocalization focused on disease models in which antibodies are key effectors of disease including rheumatoid arthritis and alloantibody-mediated hemophilia, and these studies primarily reported in vivo antibody titer data. − In type 1 diabetes (T1D), however, autoantibodies do not have such a clear role in disease, although their presence indicates risk of disease development. Rather, effector anti-islet antigen B cells are pathogenic and propagate autoimmunity via autoantigen presentation and inflammatory cytokine excretion. − In addition, these prior B cell tolerization studies have primarily relied on liposome and large polymer scaffolds bearing hundreds of copies of antigen and CD22 ligand (CD22L), and less is known about the potential of low valency antigen–CD22L conjugates to tolerize B cells in a similar manner. , …”