Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA.
Henry M. Jackson Foundation, 6720A Rockledge Drive, Bethesda, MD, 20817, USA.
Cell Death Dis. 2021 Apr 14;12(4):400. doi: 10.1038/s41419-021-03689-6.
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.
免疫稳态依赖于有效清除病原体，同时防止宿主发生自身免疫和免疫病理学。再刺激诱导的细胞死亡（RICD）就是这样一种机制，其中激活的 T 细胞接受随后的抗原刺激，通过 T 细胞受体（TCR）达到临界信号阈值，并决定细胞凋亡。这个过程的许多细节仍然不清楚，包括影响 TCR 信号级联的共刺激和共抑制蛋白的作用。在这里，我们描述了 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM-3）在 RICD 调节中的作用。TIM-3 保护新激活的 CD8 效应 T 细胞在克隆扩增过程中免于过早发生 RICD。然而，令人惊讶的是，我们发现 TIM-3 增强了晚期效应 T 细胞的 RICD。TIM-3 的存在增加了晚期效应 T 细胞中 TCR 信号的近端和促凋亡蛋白的表达，而在有或没有 TIM-3 的新激活细胞中，没有观察到一致的信号效应。为了更好地解释 TIM-3 作为 T 细胞老化时功能的差异，我们描述了效应 T 细胞中 TIM-3 表达的时间模式。我们发现 TIM-3 表达在新激活的效应 T 细胞表面，但在晚期效应细胞中主要位于细胞内。这与 TIM-3 需要配体来防止早期 RICD 的事实一致，而配体处理在后期阶段没有影响。在已知的 TIM-3 配体中，癌胚抗原相关细胞粘附分子 1（CEACAM1）在时间上的表面表达差异最大，并且也能保护新激活的细胞免于过早发生 RICD，而对晚期效应器没有可测量的影响。事实上，CEACAM1 使 T 细胞表面表达 TIM-3，这意味着这两种蛋白在保护扩增的 T 细胞免于过早发生 RICD 方面存在共依赖性。我们的发现表明，共信号蛋白如 TIM-3 和 CEACAM1 可以改变效应 T 细胞反应不同阶段的 RICD 敏感性，这对检查点阻断治疗具有重要意义。
