Type I or insulin dependent diabetes mellitus develops in the non-obese diabetic (NOD) mouse as a consequence of T cell mediated autoimmune attack on pancreatic beta cells. B lymphocytes are required for disease progression in NOD and loss of tolerance in the B cell compartment is one of the earliest manifestation of the autoimmune process. To understand how the fate and function of B lymphocytes may be regulated in the context of an organ specific autoimmune disease, the B cell co-receptor CD72 (Lyb-2) was examined in NOD mice. Mab that recognize a,b, and d alleles of CD72 reacted poorly with NOD B cells while western blots of B cell extracts show that CD72 is abundant in NOD B cells. Nucleotide sequencing of CD72 cDNA confirms that an uncommon allele, CD72c, is expressed in NOD. Functional studies using monoclonal antibodies indicate that the CD72c allele of NOD can serve as a positive regulator of B cell responses both as a single signal and in synergy with BCR or IL-4 stimulation. Since CD72c differs principally in the extra cellular or ligand binding portion of the molecule, interactions with its natural ligand in vivo may contribute to functional differences in mouse strains that express this allele. NOD and lupus prone strains share the CD72c allele and its functions may contribute to overlapping features of organ specific and systemic autoimmune disorders.