TIM-3 drives temporal differences in restimulation-induced cell death sensitivity in effector CD8+ T cells in conjunction with CEACAM1

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.

Increased CEACAM1 expression on peripheral blood neutrophils in patients with rheumatoid arthritis

“…CEACAM1 is an ITIM type 1 membrane protein and its main functional role in lymphocytes is to generate inhibitory signals ( 28 ); however, the inhibitory effects of CEACAM1 have not been completely elucidated. CEACAM1 can bind to TIM–3 intracellularly, which appears to be important for the function of TIM–3 ( 29 ). In vitro , CEACAM1 is co–expressed with TIM–3 in activated T cells and is thought to contribute to the establishment of T–cell tolerance ( 30 ).…”

Expression changes of Tim-3 as one of supplementary indicators for monitoring prognosis of liver pathological changes in chronic HBV infection

“…Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a ligand of Tim-3 that is necessary to mediate the suppressive function of T cells [ 34 ]. Binding of Tim-3 and CEACAM1 promotes temporal differences in Restimulation-induced cell death (RICD) sensitivity in the effector T cell response [ 35 ], which plays a key role in regulating anti-tumour immunity [ 34 ] and antiviral responses [ 36 ]. As another Tim-3 ligand, phosphatidylserine (PtdSer) may play a crucial role in regulating tolerance by clearing apoptotic cells [ 37 , 38 ] and enhancing cross-antigen presentation [ 39 ].…”

Immune Checkpoint Receptors Signaling in T Cells

“…TIM-3 presents a membrane distal Ig-like V domain involved in ligand interactions, a membrane proximal mucin domain, and a transmembrane domain connected to an intracellular cytoplasmic tail involved in phosphotyrosine-dependent signaling. TIM-3 is a promiscuous receptor suggested to bind heterologous ligands, such as phosphatidylserine, from apoptotic cells [ 69 ], carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1, [ 70 ]), the alarmin protein high mobility group B1 (HMGB1), and the carbohydrate receptor galectin-9 [ 71 ]. Tim-3 is actively recruited to the IS, where it associates with other transmembrane proteins, including the CD45 and CD148 phosphatases, which may perturb IS stability [ 72 , 73 ].…”

“…The intracellular Tim-3 signaling in T cells depends on its cytoplasmic tail but is poorly defined and may be different between ligand-bound, plasma membrane recruited Tim-3 and the pool residing in intracellular vesicles upon exhaustion [ 70 ]. A recent proteomic study indicated a coprecipitation of Tim-3 with 37 proteins, of which 11 are dynamically regulated by pervanadate, including the E3 ubiquitin ligase CBL-B, SHP-1, and Grb2 [ 72 ].…”