Li et al. showed that grafts of nucleated hematopoietic cells lacking expression of homotypic SLAM family receptors (SFR), notably SLAMF3 and SLAMF4, were cleared by phagocytic WT macrophages triggered in part by their LRP1 “eat-me receptors” to induce mTORC1 and Syk through SHP-1/2. SFR deficiency of hosts reduced hematopoietic tumor burden in murine models, and led to more severe TLR agonist-induced murine hemocytopenia. CAR-modified macrophages from SFR-negative hosts, or antibody blockade of SLAMF2 (a ligand for SLAMF3) and/or SLAMF3 increased phagocytosis of CD19+ targets in vitro.
Contributed by Paula Hochman
ABSTRACT: The interaction of SIRPα with CD47 represents a major mechanism for preventing macrophage phagocytosis. However, CD47-independent mechanisms are poorly defined. Here, we report a critical role of SLAM family receptors (SFRs), ubiquitously expressed on hematopoietic cells and forming homotypic interactions, in constraining macrophage phagocytosis. We found that SFR deficiency triggered macrophage phagocytosis of hematopoietic cells, leading to severe rejection of donor hematopoietic graft in recipient mice. Specific SFR members, mainly SLAMF3 and SLAMF4, were identified as "don't eat me" receptors on macrophages. These receptors inhibited "eat me" signals, such as LRP1-mediated activation of mTOR and Syk, through SH2 domain-containing phosphatases. SFRs combined with, but were independent of, CD47 to mitigate macrophage phagocytosis, and the combined deletion of SFRs and CD47 resulted in hematopoietic cytopenia in mice. This SFR-mediated tolerance was compromised in patients with hemophagocytic lymphohistiocytosis, a syndrome characterized by inappropriate phagocytosis toward hematopoietic cells. Loss of SFRs potently elicited macrophage rejection of hematopoietic tumors. Deletion of SFRs also significantly enhanced the phagocytosis of CD19-positive hematopoietic targets by the macrophages expressing the chimeric CD19 antigen receptor. Therefore, SFR-mediated inhibition of macrophage phagocytosis is critical to hematopoietic homeostasis, and SFRs may represent previously unknown targets for tumor immunotherapy.
Author Info: (1) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (2) School of Medic
Author Info: (1) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (2) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (3) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (4) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (5) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. (6) Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. (7) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (8) Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China. (9) Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. (10) First Bethune Hospital and International Center of Future Science, Jilin University, Changchun 130061, China. (11) Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (12) Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (13) School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. School of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 271016, China.
