TIM-4 is a type-I transmembrane protein composed of an extracellular, RGD motif-containing Ig domain, a mucin domain, and an intracellular tail. TIM-4 is expressed on antigen-presenting cells (APC), including dendritic cells and macrophages in spleen and lymph nodes, and on resident macrophages and B-1 cells of the peritoneal cavity. TIM-4 has been shown to bimodally regulate T-cell immunity by both inhibiting naïve T cells during T cell priming and expanding activated T cells during the effector phase of the immune response. In accordance with the latter, we found that TIM-4 could costimulate T cell proliferation by enhancing the phosphorylation of key T cell signaling molecules, such as LAT and Akt, along with TIM-1, a TIM-4 binding partner expressed on activated T cells. TIM-4 is also a receptor for phosphatidylserine, a phospholipid exposed on apoptotic bodies (AB). We generated TIM-4 ^-/- mice and observed a niche-specific defect in AB clearance in that peritoneal APC, but not splenic or lymph node APC, had an impaired ability to uptake AB. Accordingly, TIM-4^-/- mice show a hyperproliferative T and B cell response, with increased titers of serum immunoglobulin, and the spontaneous development of anti-dsDNA autoantibodies. Paradoxically, intraperitoneal immunization of TIM-4^-/- mice revealed a defect in T cell responses in the mesenteric lymph nodes, suggesting that TIM-4 effects on T cell immunity might also be niche-specific. Similarly, skin sensitization of TIM- ^-/- mice resulted in the defective development of contact hypersensitivity responses. The defect in priming T cell responses in TIM-^-/- mice appears to be partly due to impaired migration of local APC to the draining lymph nodes. Therefore, TIM-4 has important immunoregulatory roles in both the innate and adaptive immune systems. In the adaptive immune system, TIM-4 directly regulates the expansion of T cells by binding to its receptors expressed on T cells, and affects the balance between tolerance and autoimmunity to self-antigens acquired through the uptake of dying cells. In the innate immune system, TIM-4 may play a role in regulating the migration of APC from various tissue niches, consequently affecting downstream immune responses in draining lymph nodes.