Diverse roles of TIM4 in immune activation: implications for alloimmunity

T-cell immunoglobulin and mucin domain-containing molecule (TIM)4 is a costimulatory molecule and phosphatidylserine receptor. Its dominant function varies according to the expressing cell and site of activation. In recent years, studies have identified its role in diverse disease processes and increasingly in alloimmunity. Herein, we will comprehensively review the literature on TIM4 and outline its function in shaping the alloimmune response.

TIM4 expression on dendritic cells increases following transplantation. Blockade of TIM4 in vivo leads to increased differentiation of regulatory T cells and improved allograft survival. TIM4 binds phosphatidylserine-expressing apoptotic cells. Previously thought of as a tethering molecule, recent studies have demonstrated that TIM4 interacts with integrins to mediate uptake of apoptotic cells. TIM4 B cells have recently been identified, which produce high levels of IFNγ and promote allograft rejection. Targeting these B cells improved allograft survival and promoted the development of TIM1 regulatory B cells.

TIM4 is expressed in niche compartments and has many immunological effects. However, inhibition of TIM4 has been demonstrated to prolong allograft survival, through varied mechanisms. A unifying explanation for the role of TIM4 in alloimmunity remains to be found, but this pathway appears to hold considerable promise in transplantation.