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Blockade of Tim‐4 Aggravates Atherosclerosis
Author(s) -
Foks Amanda,
Engelbertsen Daniel,
AlbertsGrill Noah,
Kuperwaser Felicia,
DeKruyff Rosemarie,
Freeman Gordon,
Lichtman Andrew
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.418.3
Subject(s) - immune system , antibody , phagocytosis , t cell , apoptosis , cd40 , immunology , microbiology and biotechnology , biology , chemistry , in vitro , cytotoxic t cell , biochemistry
Introduction Proteins of the transmembrane T cell immunoglobulin and mucin domain (Tim) family are expressed by numerous immune cells, recognize phosphatidylserine (PS) exposing cells and exert either a costimulatory or coinhibitory role. Tim‐4, present on macrophages and antigen‐presenting cells, has been shown to play a critical role in the clearance of apoptotic cells, regulates the number of PS‐expressing activated T cells, and is genetically associated with triglyceride levels. Since both apoptosis and the presence of activated T cells contribute to atherosclerotic lesion formation, we investigated whether interference in Tim‐4 function would affect atherosclerosis. Methods and Results LDLr ‐/‐ mice were fed a Western‐type diet for 4 weeks while being treated twice a week i.p. with an anti‐Tim‐4 (21H12) mAb that blocks PS recognition and phagocytosis or an isotype control (rat IgG1). Treatment with anti‐Tim‐4 increased the area of atherosclerotic lesion in the aortic root by 52% (8.58±1.40%) compared with control mice (5.69±0.51%, P <0.01), independent of plasma cholesterol and triglyceride levels. Anti‐Tim‐4‐treated mice showed increased activated T cell numbers and ‘late’ apoptotic cells in the circulation. Additionally, anti‐Tim‐4 treatment induced splenomegaly, enhanced splenocyte proliferation and increased IFNγ + (Th1) and IL‐4 + (Th2) cells. Conclusion Blockade of Tim‐4 aggravates atherosclerosis likely by prevention of phagocytosis of PS‐expressing apoptotic cells and activated T cells by Tim‐4‐expressing cells.