Abstract
Immune homeostasis depends upon effective clearance of pathogens while simultaneously preventing autoimmunity and immunopathology in the host. Restimulation-induced cell death (RICD) is one such mechanism where by activated T cells receive subsequent antigenic stimulation, reach a critical signal threshold through the T cell receptor (TCR), and commit to apoptosis. Many details of this process remain unclear, including the role of co-stimulatory and co-inhibitory proteins that influence the TCR signaling cascade. Here we characterize the role of T cell immunoglobulin and mucin domain containing 3 (TIM-3) in RICD regulation. TIM-3 protected newly activated CD8+ effector T cells from premature RICD during clonal expansion. Surprisingly, however, we found that TIM-3 potentiated RICD in late-stage effector T cells. The presence of TIM-3 increased proximal TCR signaling and proapoptotic protein expression in late-stage effector T cells, with no consistent signaling effects noted in newly activated cells with or without TIM-3. To better explain these differences in TIM-3 function as T cells aged, we characterized the temporal pattern of TIM-3 expression in effector T cells. We found that TIM-3 was expressed on the surface of newly activated effector T cells, but remained largely intracellular in late-stage effector cells. Consistent with this, TIM-3 required a ligand to prevent early RICD, whereas ligand manipulation had no effects at later stages. Of the known TIM-3 ligands, carcinoembryonic antigen‐related cell adhesion molecule (CEACAM1) showed the greatest difference in surface expression over time and also protected newly activated cells from premature RICD, with no measurable effects in late-stage effectors. Indeed, CEACAM1 enabled TIM-3 surface expression on T cells, implying a co-dependency for these proteins in protecting expanding T cells from premature RICD. Our findings suggest that co-signaling proteins like TIM-3 and CEACAM1 can alter RICD sensitivity at different stages of the effector T cell response, with important implications for checkpoint blockade therapy.
Highlights
Restimulation-induced cell death (RICD) is a homeostatic process through which a proportion of T cells restimulated through their T cell receptor (TCR) succumb to apoptosis, enforcing peripheral tolerance and establishingOfficial journal of the Cell Death Differentiation AssociationLake et al Cell Death and Disease (2021)12:400 ensure a healthy immune response against pathogens and prevent autoimmunity.A number of mechanisms have been described which sensitize T cells to RICD
Because TIM-3 was expressed at both early and late time points in primary CD8+ effector T cells, we investigated the effect of TIM-3 siRNA-mediated silencing on RICD at both stages when cells are clonally expanding or nearing contraction
In newly activated CD8+ effector T cells, TIM-3 partners with carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1) to shield them from premature RICD, helping to ensure proper clonal expansion
Summary
Restimulation-induced cell death (RICD) is a homeostatic process through which a proportion of T cells restimulated through their T cell receptor (TCR) succumb to apoptosis, enforcing peripheral tolerance and establishingOfficial journal of the Cell Death Differentiation AssociationLake et al Cell Death and Disease (2021)12:400 ensure a healthy immune response against pathogens and prevent autoimmunity.A number of mechanisms have been described which sensitize T cells to RICD. One key driver of differential RICD sensitivity in late-stage effector T cells is relative TCR signal strength[11]; only T cells that reach a critical TCR signal threshold via strong, repeated restimulation will succumb to RICD. This insight suggests that proteins which directly regulate TCR signal strength should have a measure of influence over RICD sensitivity in effector. Tcells, though this has not been thoroughly investigated. The dependence on TCR signal strength is unclear in newly activated cells, in which the mechanisms driving RICD resistance remain largely unknown
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