Fig. 8.
Schematic summary of B-cell-directed CD8 T-cell suppression in the context of type 1 diabetes. 1. B cells from protected NOD mice stimulated via TLR4 or anti-CD40 express substantial levels of intracellular IL-10, but only TLR4 stimulation induces IL-10 secretion. 2. B cells from diabetic NOD mice express reduced levels of intracellular IL-10 when stimulated via TLR4 and lack IL-10 expression in response to anti-CD40 stimulation but can secrete IL-10 in response to TLR4 stimulation. 3. a BM–DCs engage with TLR4-activated B cells from protected NOD mice. b Upon initial engagement, a possible reciprocal contact-mediated process induces altered BM–DC to generate an IL-10 feedback loop and tolBM–DC induction by IL-10 (dotted arrows). c B cell–BM–DC contact augments IL-10 production by B cells, creating a feedback loop as shown by the solid black arrows. d B cell–BM–DC contact and IL-10 secretion induce a deactivated tolerogenic BM–DC population (tolBM–DCs). e Tolerogenic deactivated BM–DCs suppress pathogenic CD8 T cells. f The effect of tolBM–DCs on B cells after induction is still unknown (dashed arrow). 4. B cells from diabetic NOD mice have a diminished response to contact with BM–DCs, which results in fewer deactivated tolBM–DCs. 5. In the presence of CD8 T cells and proinflammatory cytokines, i.e., IFNγ, LPS-stimulated B cells from diabetic NOD mice in contact with BM–DCs amplify their IL-10 response and induce CD8 T-cell suppression as effectively as B cells from protected NOD mice