EndoU is a novel regulator of AICD during peripheral B cell selection

Poe, Jonathan C.; Kountikov, Evgueni I.; Lykken, Jacquelyn M.; Natarajan, Abirami; Marchuk, Douglas A.; Tedder, Thomas F.

BCR ligation by agonistic anti-IgM Abs induces 30-50% of spleen B cells from WT mice to blast and undergo proliferation ex vivo (DeFranco et al., 1982) . However, the threshold for B cell AICD can be influenced by genetically altering the stimulatory and inhibitory pathways that regulate BCR-induced activation (Inaoki et al., 1997) . The B cell-restricted surface protein CD22 is generally considered to negatively regulate BCR signaling by recruiting potent intracellular phosphatases after BCR ligation (Doody et al., 1995; O'Keefe et al., 1996; Otipoby et al., 1996; Sato et al., 1996; Nitschke et al., 1997; Tedder et al., 1997; Poe et al., 2000) , and CD22 / mice produce augmented levels of isotype-switched auto-Abs against DNA and some protein Ags (O'Keefe et al., 1999; Poe et al., 2011) . Nevertheless, B cells from inbred CD22 / mice with a B6/129 genetic background (CD22 / [inbr] ) are phenotypically and functionally normal ex vivo (Poe et al., 2004) . In contrast, spleen B cells from C57BL/6 (B6) mice genetically deficient in CD22 (CD22 /[B6] ) undergo AICD after BCR stimulation (Poe et al., 2004) , which is likely to be a result of their inability to induce c-Myc transcription factor expression that balances B cell proliferation versus AICD (Donjerković and Scott, 2000; Poe et al., 2004) . These striking phenotypic differences in B cells between mouse lines with a common deletion of Cd22 indicate that important B cell signaling events that promote AICD are influenced differently by the B6 and 129 genetic backgrounds. These two CD22 / mouse lines were therefore used to identify genetic and molecular factors regulating B cell AICD.