Association Between Programed Cell Death-1 and CD4+ T Cell Alterations in Different Phases of Ischemic Stroke Patients

Abstract

Objective: We aimed to analyze alterations in T cell subgroups during different post-ischemic stroke (IS) phases to explore the possible mechanisms underlying stroke-induced immune depression (SIID).Methods: Sixty-four IS patients who met the entry criteria were divided into three groups: an acute phase group, a sub-acute phase group and a stable phase group. Fourteen healthy individuals were selected as normal controls. The phenotype distribution of T cells in patient peripheral blood was analyzed, and the immune checkpoint receptors programed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) were detected in different T cell phenotypes.Results: Compared with the control group, the absolute number of CD4+ T cells and CD4+ T central memory (TCM) cells was significantly increased in the acute phase group but decreased in the sub-acute phase and stable phase groups compared with that in the acute phase group. PD-1 expression in CD4+ T cells in the stable phase group showed a significant increase compared with that in the acute phase group. The expression of PD-1 on CD4+ TCM cells and CD4+ T effector memory (TEM) cells showed significant decreases in the acute phase compared with control cells; however, in the sub-acute phase and the stable phase, PD-1 expression was significantly increased compared with that in the acute phase.Conclusions: T cell dysfunction, especially CD4+ T cell dysfunction, occurred during different IS phases. PD-1 was highly expressed in CD4+ T cells of different phenotypes after the acute phase and was associated with alterations in CD4+ T cells. Particularly, PD-1 was negatively correlated with the absolute number of TCM cells among different CD4+ T cell phenotypes, which may be one of the possible mechanisms of SIID.

The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

“…However, IL-15 was also reported to defend astrocytes against oxygen-glucose deprivation (OGD)-induced damage and death, and astrocytes could protect neurons from ischaemic injury and sustain BBB integrity [129], which are contradictory Bodhankar et al identified that PD-1 and CTLA-4 had inhibitory effects on the activation of T cells in a rodent stroke model [151] and that blockade of the PD-L1 checkpoint significantly limited the CNS inflammatory response and improved neurological outcomes by partially reversing splenic atrophy and increasing the accumulation of CD8 + Treg cells in the lesioned brain hemisphere [131]. This suggests the application potential of a novel therapy using accessible humanized anti-PD-L1 antibodies to treat human stroke subjects and confirms that PD-1 is inversely correlated with the absolute amount of CD4 + T central memory (TCM) cells in ischaemic patients [135]. However, these conclusions remain to be validated in clinical trials.…”

Elevation of Neutrophil CEACAM1 Associated with Multiple Inflammatory Mediators was Related to Different Disease Progression in Ischemic Stroke Patients

“…Thus, it could affect the Tim-3 positive T lymphocyte proliferation [29], function [46] and secretion of cytokines [31]. Our previous study indicated that there was elevation of Tim-3 on the peripheral blood T lymphocytes in the stroke [32]. We speculated that CEACAM1 could bind with Tim-3 through the T lymphocyte surface, which may induce injury of immune function of lymphocytes at the late stage IS patients, and nally result in increased risk of infection.…”

“…Moreover, it is closely related to the proliferation and apoptosis of neutrophils and lymphocytes [27][28][29], together with the secretion of cytokines [30,31]. Our previous study indicated that there was signi cant elevation of CD8 + T cell TIM-3 in the stroke patients [32], and CEACAM1 was also one of the ligands for TIM-3 [33]. NGAL is reported to be involved in the innate immunity, cellular differentiation and proliferation, as well as iron homeostasis [34].…”

A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells

“…Studies have documented increased CD69 + T cells in the palatine tonsils and cervical lymph nodes of stroke patients 76 h following stroke onset [80], and that activated T cells reactive to myelin oligodendrocyte glycoprotein accumulate in the brain following experimental stroke, implicating activated T cells in driving autoimmunity post-stroke [81,82]. Conversely, an exhausted T cell phenotype characterized by an increased frequency of PD-1 + CD4 + T cells has also been observed in patients 48 h post-stroke [83]. Given the diverse T cell phenotypes and their pleiotropic roles post-stroke, it becomes crucial to dissect mechanisms that control immunoregulatory programmes in T cells balancing the requirement for a tightly regulated anti-microbial immune response versus initiating an autoimmune reaction.…”