The Cell Surface Receptor Slamf6 Modulates Innate Immune Responses During Citrobacter Rodentium-Induced Colitis

Slamf6 exacerbates colitis caused by a Gram(-) bacterium.The homophilic cell surface receptors CD150 (Slamf1) and CD352 (Slamf6) are known to modulate adaptive immune responses. Although the T(h)17 response was enhanced inSlamf6(-/-) C57BL/6 mice upon oral infection withCitrobacter rodentium, the pathologic consequences are indistinguishable from an infection of wild-type C57BL/6 mice. Using a reporter-based binding assay, we show that Slamf6 can engage structures on the outer cell membrane of several Gram(-) bacteria. Therefore, we examined whether Slamf6, like Slamf1, is also involved in innate responses to bacteria and regulates peripheral inflammation by assessing the outcome ofC. rodentium infections inRag(-/-) mice. Surprisingly, the pathology and immune responses in the lamina propria ofC. rodentium-infectedSlamf6(-/-) Rag(-/-) mice were markedly reduced as compared with those ofRag(-/-) mice. Infiltration of inflammatory phagocytes into the lamina propria was consistently lower inSlamf6(-/-) Rag(-/-) mice than inRag(-/-) animals. Concomitant with the reduced systemic translocation of the bacteria was an enhanced production of IL-22, suggesting that Slamf6 suppresses a mucosal protective program. Furthermore, administering a mAb (330) that inhibits bacterial interactions with Slamf6 toRag(-/-) mice ameliorated the infection compared with a control antibody. We conclude that Slamf6-mediated interactions of colonic innate immune cells with specific Gram(-) bacteria reduce mucosal protection and enhance inflammation, contributing to lethal colitis that is caused byC. rodentium infections inRag(-/-) mice.