Wang, Ninghai

Abstract Signaling lymphocyte activation molecule (Slamf1) is a T cell co-stimulatory molecule and a regulator of cytokine production by macrophages and dendritic cells. Because Slamf1 positively regulates microbicidal mechanisms in macrophages, we evaluate whether Slamf1 would affect enterocolitis. To induce colitis, mouse CD45RBhi CD4+ T cells were transferred into RAG-/- or Slamf1-/- RAG-/- recipient mice. In a second set of experiments, an agonistic αCD40 antibody was administered to the same recipient strains to induce colitis. Whilst the absence of Slamf1 in RAG-/- recipients mitigated colitis, the function of disease-causing effector or regulatory T cells was not affected by the ablation of the receptor. Surprisingly, in Slamf1-/- mice monocyte / macrophage migration into the inflamed tissue was impaired not only in αCD40-induced colitis but also in two other in vivo models of inflammation: thioglycolate induced peritonitis and in an “air pouch” model in response to TNFα. Administering αSlamf1 to RAG-/- mice ameliorated enterocolitis and altered this migration. Slamf1 is a key contributor to the innate immune responses during experimental colitis by affecting the migration of monocytes / macrophages to the sites of inflammation. As αSlamf1 also mitigates the pathogenesis of colitis, SLAMF1 should be a plausible therapeutic target in treating inflammatory bowel diseases.

Abstract Macrophages eradicate pathogens by phagosomal reactive oxygen species, nitric oxide and by exposure to phagolysosomal enzymes. Whereas a number of surface receptors are requisite for recognition and entry of bacteria into the phagosome, their role in bacterial killing is largely unknown. Here we show that the surface receptor SLAM (Slamf1, Cd150) enters the macrophage phagosome together with Gram-negative, but not with Gram-positive bacteria. In the bacterial phagosome, SLAM regulates production of phosphatidylinositol-3-phosphate (PI3P), which is a key factor in the assembly of the active NADPH-oxidase (Nox2) enzyme complex, as well as in phagosome maturation. Consequently, these two bactericidal processes are defective in the absence of SLAM, resulting in an impaired clearance of attenuated S. typhimurium sseB- in SLAM-deficient mice. This is the first example of a surface receptor, which is a co-stimulatory molecule in T cell responses, also governing distinct functions in intracellular vesicles of phagocytic cells. This work was supported by a grant from the NIH (AI-15066)