Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

Abstract

SummaryAging is accompanied by altered T‐cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD‐1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T‐cell exhaustion and aging‐associated immune dysfunction. In this study, we demonstrate that T‐cell immunoglobulin mucin domain‐3 (Tim‐3), another exhaustion marker, is up‐regulated on aged T cells, especially CD8+ T cells. Tim‐3‐expressing cells also produced PD‐1, but Tim‐3+ PD‐1+ CD8+ T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim‐3− PD‐1+ cells. Tim‐3+ PD‐1+ CD8+ T cells showed more evident properties associated with exhaustion than Tim‐3− PD‐1+ CD8+ T cells: an exhaustion‐related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL‐10 and induced normal CD8+ T cells to produce IL‐10, which might contribute to immune dysregulation in aged mice. The generation of Tim‐3‐expressing CD8+ T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8+ T‐cell population with age‐associated exhaustion was distinguishable by its expression of Tim‐3. These results provide clues for understanding the alterations that occur in T‐cell populations with age and for improving dysfunctions related to the aging of the immune system.

Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study

“…Interestingly, this study was the first to reveal that the expression of TIM-3 on cytotoxic T cells significantly increased in patients with BD, which tented to negatively associate with the score of MADRS. As documented, TIM-3 not only plays a crucial role in mediating the exhaustion of cytotoxic T cells1417, but also presents as a potent suppressor of cytotoxic T cell inflammation27. Blockade of TIM-3 pathway can help to restore the adaptive immunity28.…”

“…Programmed cell death protein 1 (PD-1) also functions as an inhibitory immune checkpoint and negatively regulates immune response1516. Moreover, TIM-3 and PD-1 both may weaken CD8+ T-cell function and induce T-cell exhaustion17. PD-L1 and PD-L2, two ligands of PD-1, and their interaction with PD-1 are correlated with T cell activation and tolerance1819.…”

The immune dysfunction in ankylosing spondylitis patients

“…Tim-3 and PD-1 take part in control negative regulation of immune responses in many diseases (34), establishing the balance between the activation and inhibition of T cells, with a tendency towards the latter. We found that the expression of Tim-3 on CD4 + T cells and PD-1 on CD8 + T cells was notably lower in AS, which implied that Tim-3 and PD-1 on T cells could affect the disease.…”

Successful and Maladaptive T Cell Aging

“…While exhausted CD8 + T cells triggered by just age in the absence of infection have been described in the mouse, similar evidence for humans is lacking (Lee et al, 2016). However, some of the pathways that induce T cell exhaustion may be shared with those that are involved in T cell aging and senescence.…”