TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells

Abstract

Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80+ lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance.

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

“…38 TIM4 does not have any signaling motif in its cytoplasmic domain but promotes engulfment of activated antigen-specific T cells, 39 as well as apoptotic cells, 11,12 via PS recognition by utilizing b1 integrins as co-receptors. 40 Deficiency of TIM4 expression is linked to reduced tolerance, 39 enhanced tumor immunity 41 and the development of autoimmunity. 12 Another PS receptor, BAI1, mediates engulfment of apoptotic cells, but unlike TIM4, directly activates downstream signaling events.…”

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

“…Tim4 has recently been shown to regulate T-cell populations during the resolution of an immune response by mediating the PS-dependent phagocytosis of both apoptotic and nonapoptotic antigen-specific T cells (15,16). In one capacity, Tim4 initiates the highly selective and thorough clearance of apoptotic T cells by virtue of the exposure of high levels of PS on their surfaces (15,20,21).…”

“…Equally important, however, is that Tim4 is also instrumental in pruning the population size of activated, but nonapoptotic, T cells. This activated T-cell removal is important for both immune tolerance in the lungs (16) and the maintenance of an appropriately sized pool of memory T cells after viral infection (15). Although nonapoptotic T-cell removal is believed to occur via the same PSdependent mechanisms as apoptotic cell phagocytosis, it must necessarily be done with less vigor to ensure the appropriate level of controlled regulation (15,16).…”

“…purposes of phagocytic removal (15,16,(20)(21)(22). The crystal structure of Tim4 in complex with a single-PS head group has provided invaluable insight into how Tim4 specifically recognizes a single-PS molecule (23).…”

“…Addressing this central question has been exceedingly difficult, given that the standard tools of structural immunology are not well suited to characterizing dynamic membrane systems. Nevertheless, it appears that the ability to discern apoptotic versus nonapoptotic instances of PS exposure may indeed be a required feature of at least one PS receptor, T cell immunoglobulin and mucin-domain-containing molecule 4 (Tim4) (15,16).…”