I-A(g7)-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice
H. Noorchashm et al., I-A(g7)-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice, J IMMUNOL, 163(2), 1999, pp. 743-750
B cell-deficient nonobese diabetic (NOD) mice are protected from the develo
pment of spontaneous autoimmune diabetes, suggesting a requisite role for A
g presentation by B lymphocytes for the activation of a diabetogenic T cell
repertoire. This study specifically examines the importance of B cell-medi
ated MHC class II Ag presentation as a regulator of peripheral T cell toler
ance to islet beta cells. We describe the construction of NOD mice with an
I-A(g7) deficiency confined to the B cell compartment. Analysis of these mi
ce, termed NOD B-CIID, revealed the presence of functionally competent non-
B cell APCs (macrophages/dendritic cells) with normal I-A(g7) expression an
d capable of activating Ag-reactive T cells. In addition, the secondary lym
phoid organs of these mice harbored phenotypically normal CD4(+) and CD8(+)
T cell compartments. Interestingly, whereas control NOD mice harboring I-A
(g7)-sufficient B cells developed diabetes spontaneously, NOD B-CIID mice w
ere resistant to the development of autoimmune diabetes, Despite their diab
etes resistance, histologic examination of pancreata from NOD B-CIID mice r
evealed foci of noninvasive peri-insulitis that could be intentionally conv
erted into a destructive process upon treatment with cyclophosphamide. We c
onclude that I-A(g7)-mediated Ag presentation by B cells serves to overcome
a checkpoint in T cell tolerance to islet beta cells after their initial t
argeting has occurred. Overall, this work indicates that the full expressio
n of the autoimmune potential of anti-islet T cells in NOD mice is intimate
ly regulated by B cell-mediated MHC class II Ag presentation.