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

If there is any useful information in here I don't understand it. Our fucking failures of stroke associations should be translating all stroke research into readable and actionable formats. A database of stroke research and stroke protocols would be the easy way to do this, but will never occur until survivors run everything. 

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

Yi Zhang^1†, Li Wei^2†, Yupeng Du³, Yirui Xie², Wei Wu^2* and Yuan Yuan^4*

• ¹Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
• ²State Key Laboratory of Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
• ³Department of Rehabilitation, The Third Affiliated Hospital, Zhejiang University of Traditional Chinese Medicine, Hangzhou, China
• ⁴Department of Neurology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China

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).
(Maybe depression occurs because survivors are given no way to get 100% recovered. Use Occam's razor.)

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.

Introduction

Stroke is a disease associated with high death and disability worldwide and results in permanent neurological damage to patients (Strong et al., 2007). Ischemic stroke (IS), which accounts for 80%–85% of stroke cases, is frequently induced by thromboembolic occlusion of the cerebral artery. In particular, infectious complications have been reported to occur in 23%–65% of stroke patients after stroke, which leads to poor recovery of patients (Chamorro et al., 2007).

The immune system is considered to play critical roles in patient outcomes following stroke, including in acute stroke events and long-term post-stroke recovery (Bravo-Alegria et al., 2017). In a mouse model, Prass et al. (2003) reported that stroke induced immunodeficiency, which increases susceptibility to bacterial infections. In a human study, impaired T cell responses and decreases in peripheral lymphocyte counts have been reported in stroke patients (Haeusler et al., 2008).

IS induces two immunological cascades: an autoimmune response to central nervous system (CNS) antigens that induces brain inflammation and stroke-induced immunodepression (SIID), which impairs resistance to bacterial infections, resulting in increased incidence of infection, particularly urinary tract infections and pneumonia (Vogelgesang and Dressel, 2011). However, the mechanisms leading to SIID remain unclear, which seriously affects prevention and control of infectious complications in the clinic.

T cell immunity is involved in IS. T cell, but not B cell, contributions to inflammatory and thrombogenic responses have been reported in mice IS (Yilmaz et al., 2006). Chamorro et al. (2005) reported that T cells shift from a Th1-type response to a Th2-type response post-stroke phase. Tregs have been reported to reduce the infarct volume in rats subjected to transient brain ischemia. Dolati et al. (2018) reported that increased Th17 cells and decreased Tregs might contribute to the pathogenesis of IS. Furthermore, accumulating evidence has shown that T cells play important roles in the stroke process (Ishibashi et al., 2002).

T cells are classified as naïve, effector, or memory cells according to the expression of CD45 isoforms and CCR7, a chemokine receptor that helps T cells home to lymph nodes (Ebert et al., 2005). Memory T cells in the context of persistent herpes virus infection contribute to relative control and immunosurveillance of active replication or viral reactivation (Torti and Oxenius, 2012). Effector T cells have a superior capacity to respond quickly to antigenic stimulation compared with naïve T cells (Sallusto and Lanzavecchia, 2009). However, the roles of effective/memory T cells in stroke currently remain unclear. Low numbers of T lymphocytes flow into the healthy brain; however, the role of these cells in stroke is not well understood but has increasingly attracted the attention of researchers (Gemechu and Bentivoglio, 2012).

Our research group previously reported that programed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) are important cell surface markers that play key roles in immune responses. In addition, Zhao et al. (2011) reported that an increase in Tim-3 is positively correlated with IL-17 and TNF-α levels in IS. Ren et al. (2011) reported that the PD-1 pathway limited CNS inflammation and neurologic deficits in an animal stroke model. Therefore, we hypothesized that PD-1/Tim-3 may be associated with T cell alterations in stroke, which may be one of the mechanisms of SIID.

Therefore, to verify our hypothesis and explore the mechanisms underlying SIID, we investigated T cell alterations during different post-stroke phases and the correlations of PD-1 and Tim-3 with the T cell alterations.