Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice

Research output: Contribution to journalArticle


Objective - T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of phosphatidylserine-expressing activated T cells, and is genetically associated with low low-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. Approach and Results - ldlr-/- mice were fed a high-fat diet for 4 weeks while being treated with control (rat immunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that block phosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhanced atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4+T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cells and late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatment increased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. Conclusions - Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating regulatory T cells.


  • Amanda C. Foks
  • Daniel Engelbertsen
  • Felicia Kuperwaser
  • Noah Alberts-Grill
  • Ayelet Gonen
  • Joseph L. Witztum
  • James Lederer
  • Petr Jarolim
  • Rosemarie H. Dekruyff
  • Gordon J. Freeman
  • Andrew H. Lichtman
External organisations
  • University of California, San Diego
  • Stanford University
  • Dana-Farber Cancer Institute
  • Brigham and Women's Hospital, Boston
Research areas and keywords


  • apoptosis, atherosclerosis, inflammation, macrophage, T cells, Tim
Original languageEnglish
Pages (from-to)456-465
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number3
Publication statusPublished - 2016 Mar 1
Publication categoryResearch
Externally publishedYes