TY - JOUR
T1 - SLAMF9 regulates pDC homeostasis and function in health and disease
AU - Sever, Lital
AU - Radomir, Lihi
AU - Strim, Kristin
AU - Weiner, Anna
AU - Shchottlender, Nofar
AU - Lewinsky, Hadas
AU - Barak, Avital F.
AU - Ben-Dor, Shifra
AU - Becker-Herman, Shirly
AU - Shachar, Idit
N1 - The authors thank Prof. Steffen Jung for his support, Dilan Köneş and Efrat Hagai for help on the project, and members of the I.S. laboratory for fruitful discussion and support. I.S. is the incumbent of the Dr. Morton and Ann Kleiman Professorial Chair. This research was supported by the German Cancer Research Center–Israeli Ministry of Science and Technology cooperation in cancer research, ERA-NET TRANSCAN-2 program JTC 2014–project FIRE-CLL, and Binational Science Foundation Grant 711979. L.S. was supported by the Azrieli fellow program funded by The Azrieli Foundation. G.F. is the Incumbent of the David and Stacey Cynamon Research fellow Chair in Genetics and Personalized Medicine.
PY - 2019/8/13
Y1 - 2019/8/13
N2 - SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9(-/-) mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-alpha and TNF-alpha production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9(-/-) mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.
AB - SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9(-/-) mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-alpha and TNF-alpha production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9(-/-) mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.
U2 - https://doi.org/10.1073/pnas.1900079116
DO - https://doi.org/10.1073/pnas.1900079116
M3 - مقالة
SN - 0027-8424
VL - 116
SP - 16489
EP - 16496
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -