CD4+ T cells promote delayed B cell responses in the ischemic brain after experimental stroke

CD4⁺ T lymphocytes are key mediators of tissue damage after ischemic stroke. However, their infiltration kinetics and interactions with other immune cells in the delayed phase of ischemia remain elusive. We hypothesized that CD4⁺ T cells facilitate delayed autoreactive B cell responses in the brain, which have been previously linked to post-stroke cognitive impairment (PSCI). Therefore, we treated myelin oligodendrocyte glycoprotein T cell receptor transgenic 2D2 mice of both sexes with anti-CD4 antibody following 60-minute middle cerebral artery occlusion and assessed lymphocyte infiltration for up to 72 days. Anti-CD4-treatment eliminated CD4⁺ T cells from the circulation and ischemic brain for 28 days and inhibited B cell infiltration into the brain, particularly in animals with large infarcts. Absence of CD4⁺ T cells did not influence infarct maturation or survival. Once the CD4⁺ population recovered in the periphery, both CD4⁺ T and B lymphocytes entered the infarct site forming follicle-like structures. Additionally, we provide further evidence for PSCI that could be attenuated by CD4 depletion. Our findings demonstrate that CD4⁺ T cells are essential in delayed B cell infiltration into the ischemic brain after stroke. Importantly, lymphocyte infiltration after stroke is a long-lasting process. As CD4 depletion improved cognitive functions in an experimental set-up, these findings set the stage to elaborate more specific immune modulating therapies in treating PSCI.     

Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion

This study describes local immune responses in cerebral ischemia induced by permanent occlusion of the middle cerebral artery (MCAO) in the rat. The temporal and spatial pattern of leukocyte infiltration was characterized immunocytochemically using monoclonal antibodies against CD5, a pan T cell marker, against CD4 and CD8 for subtyping of T lymphocytes, and ED1, a marker for macrophages. CD5⁺ T cells were present in some animals on the pial surface at day 1 and with increasing numbers mainly at the edges of the infarcts all days 3 and 7. By day 14 their number had significantly decreased. Subtyping of T lymphocytes revealed that CD4⁺ helper/inducer T cells were rare, while CD8⁺ lymphocytes were abundant. Moreover, CD8⁺ lymphocytes outnumbered CD5⁺ T cells indicating the presence of CD5⁻/CD8⁺ natural killer (NK) cells. ED1⁺ macrophages primarily infiltrated the core of the infarct starting on day 1. Infiltrating leukocytes expressed leukocyte function associated antigen-1 and MHC class I and II antigens. Early after infarction, increased expression of the intercellular adhesion molecule-1 was found on vessel and leukocytes. In conclusion, this study shows that lymphocytes enter the nervous system not only in autoimmune diseases, but also in response to primarily ‘non-immune’ neuronal damage such as stroke.     

Lymphocyte subsets in pediatric migraine

Aseptic inflammation due to activated immune cells has been implicated in the pathomechanism of migraine. We measured the prevalence of regulatory T cells (Tregs), along with that of CD4⁺/CD8⁺ lymphocytes and their Th1/Th2 commitment in pediatric migraine. Children and adolescents suffering from migraine without aura, migraine with aura and hemiplegic migraine ictally (n = 53, 27, and 20, respectively), also interictally (n = 33) were recruited and compared to 24 healthy children. Our results indicated comparable prevalence of Tregs, CD4⁺ and Th1/Th2 committed cells. CD8⁺ prevalence was lower, and CD4⁺/CD8⁺ ratio was higher in ictal phase irrespective of the subtype of migraine. No association between CD8⁺ prevalence and gender, body weight, disease onset and attack duration in migraine subtypes was found. CD8⁺ prevalence was normal in patients in interictal phase. These results suggest the absence of major systemic alteration of adaptive immunity in children and adolescents suffering from migraine; however, a transient decrease of CD8⁺ prevalence during the ictal phase was detected irrespective of the subtype of migraine.     

卒中T淋巴细胞亚群动态变化及其与卒中相关感染的关系

目的 观察卒中急性期患者外周血中C D 3 +T细胞、C D 3 + C D 4 +T细胞、C D 3 + C D 8 +T细胞及 CD4+CD25+FoxP3+调节性T细胞（regulatory T cells,Tregs）的动态变化,探讨卒中后机体免疫状态及其 对卒中后感染的影响。 方法 选取卒中急性期患者32例为卒中组,根据发病1周内是否发生感染,将患者分为卒中后非感 染组24例和卒中后感染组8例。另选取性别、年龄匹配的健康体检者23例为对照组。采用流式细 胞术分别于病程24 h内、3 d、7 d检测卒中患者和健康体检者外周血中CD3+T细胞、CD3+CD4+T细胞、 CD3+CD8+T细胞及Tregs水平。 结果 ① 与对照组比较,卒中后非感染组CD3+CD4+T细胞与Tregs于发病后7 d升高（P分别为0.02和 0.03）;CD3+CD8+T细胞在发病后24 h及3 d下降（P分别为0.01和0.03）,发病后7 d升至与健康对照组 无显著差异。卒中后感染组CD3+T细胞、CD3+CD4+T细胞、CD3+CD8+T细胞及Tregs在发病24 h内（P分别为 ＜0.001,＜0.001,0.03和＜0.001）、3 d（P均＜0.001）、7 d（P分别为＜0.001,0.01,0.01和0.01）均较健 康对照组明显下降;②卒中后感染组CD3+T细胞、CD3+CD4+T细胞及Tregs在发病后24 h内（P分别为0.01, ＜0.001和＜0.001）、3 d（P分别＜0.001,＜0.001和0.04）、7 d（P均＜0.001）均显著低于卒中后非感染 组;两组CD3+CD8+T细胞在发病后24 h内无明显差异,但3 d（P＜0.001）、7 d（P =0.02）卒中后感染组显 著低于卒中后非感染组。 结论 C D3+T淋巴细胞、CD3+CD4+T淋巴细胞、CD3+CD8+T淋巴细胞及Tregs参与卒中早期病理生理过 程,其动态变化可能导致卒中后免疫抑制,并参与卒中后感染的发生。     

Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders

This study analyzed the populations of three different subsets of regulatory B cells (Bregs) in the peripheral blood mononuclear cells (PBMCs) of patients with neuromyelitis optica spectrum disorders (NMOSDs) and explored the relationship between the changes in these subsets of Bregs and the severity of NMOSD. A total of 22 patients with relapsed NMOSDs before treatment were recruited in our study, along with 20 age and gender-matched healthy controls, from May 2015 to March 2016. The percentages and numbers for three different subsets of Bregs including the CD19⁺CD24^hiCD38^hi, CD19⁺CD24^hiCD27⁺, and CD19⁺CD5⁺CD1d^hi populations were evaluated in parallel by flow cytometry. Afterwards, correlations between the change of three different subsets of Bregs and disease severity were analyzed. We found significantly lower percentages of CD19⁺CD24^hiCD38^hi and CD19⁺CD5⁺CD1d^hi Bregs in NMOSDs patients than in healthy individuals. In contrast, the CD19⁺CD24^hiCD27⁺ Bregs population was significantly higher in NMOSDs patients than in healthy individuals. However, the three different Bregs subsets showed no significant correlation with expanded disability status scale (EDSS) or annualized relapse rate (ARR). Our findings suggest that the subsets of Bregs may play complex roles in the pathogenesis of NMOSDs and are not correlated with clinical disease severity. Further insights into the potential role of subsets of Bregs could increase our basic knowledge of NMOSDs pathogenesis.     

Regulatory T cells increased while IL-1β decreased during antidepressant therapy

Background

Regulatory T cells (Tregs, CD4⁺CD25^hi) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1β, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4⁺CD25^hi Tregs in these immunological processes during antidepressant therapy.

Methods

16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctor’s choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1β, and measured IL-1β, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4⁺CD25^hi Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21).

Results

HAMD-21 score, IL-1β serum levels as well as LPS-stimulated IL-1β and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4⁺CD25^hi cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed.

Conclusions

The increase in CD4⁺CD25^hi Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.     

Reduction of rat brain CD8+ T‐cells by levodopa/benserazide treatment after experimental stroke

The activation of inflammatory cascades in the ischemic hemisphere impairs mechanisms of tissue reorganization with consequences for recovery of lost neurological function. Recruitment of T‐cell populations to the post‐ischemic brain occurs and represents a significant part of the inflammatory response. This study was conducted to investigate if treatment with levodopa, potentially acting as an immunomodulator, affects the T‐cell accumulation in the post‐ischemic brain. Male Sprague–Dawley rats were subjected to transient occlusion of the middle cerebral artery (tMCAO) for 105 min followed by levodopa/benserazide treatment (20 mg/kg/15 mg/kg) for 5 days initiated on day 2 post‐stroke. One week after tMCAO, T‐cell populations were analysed from brains, and levels of interleukin (IL)‐1β, chemokine (C‐X‐C motif) ligand 1, IL‐4, IL‐5, interferon gamma and IL‐13 were analysed. After levodopa/benserazide treatment, we found a significant reduction of cytotoxic T‐cells (CD3⁺CD8⁺) in the ischemic hemisphere together with reduced levels of T‐cell‐associated cytokine IL‐5, while other T‐cell populations (CD3⁺, CD3⁺CD4⁺, CD3⁺CD4⁺CD25⁺) were unchanged compared with vehicle‐treated rats. Moreover, a reduced number of cells was associated with reduced levels of intercellular adhesion molecule 1, expressed in endothelial cells, in the infarct core of levodopa/benserazide‐treated animals. Together, we provide the first evidence that dopamine can act as a potential immunomodulator by attenuating inflammation in the post‐ischemic brain.     

Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO

Local and peripheral immune responses are activated after ischemic stroke. In our present study, we investigated the temporal distribution, location, induction, and function of regulatory T cells (Tregs) and the possible involvement of microglia, macrophages, and dendritic cells after middle cerebral artery occlusion (MCAO). C57BL/6J and Foxp3^EGFP transgenic mice were subjected to 30 minutes MCAO. On days 7, 14, and 30 after MCAO, Tregs and antigen presenting cells were analyzed using fluorescence activated cell sorting multicolor staining and immunohistochemistry. A strong accumulation of Tregs was observed on days 14 and 30 in the ischemic hemisphere accompanied by the elevated presence and activation of microglia. Dendritic cells and macrophages were found on each analyzed day. About 60% of Foxp3⁺ Tregs in ischemic hemispheres were positive for the proliferation marker Ki-67 on days 7 and 14 after MCAO. The transfer of naive CD4⁺ cells depleted of Foxp3⁺ Tregs into RAG1^−/− mice 1 day before MCAO did not lead to a de novo generation of Tregs 14 days after surgery. After depletion of CD25⁺ Tregs, no changes regarding neurologic outcome were detected. The sustained presence of Tregs in the brain after MCAO indicates a long-lasting immunological alteration and involvement of brain cells in immunoregulatory mechanisms.     

Changes in peripheral blood lymphocyte subset frequencies in myasthenia gravis patients are related to immunosuppression

Surface antigens on peripheral blood lymphocytes from myasthenia gravis patients were investigated. The expression of DR⁺ and CD8⁺/DR⁺ T lymphocytes was increased and the expression of CD4⁺ T cells reduced. Neither thymectomy, clinical condition nor anti-acetylcholine receptor antibody titre correlated with any of the changes in peripheral blood lymphocyte subsets observed. However, immunosuppressive therapy correlated with the significant reduction in CD4⁺ and CD2⁺/CD4⁺ T cells in these patients.     

Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid

The distribution of lymphocyte subpopulations in cerebrospinal fluid (CSF) and their phenotypic characteristics were extensively investigated in a group of 18 healthy individuals using two- and three-color flow cytometry. Generally, CDS⁺ T lymphocytes constituted the vast majority of CSF lymphocytes while the number of B lymphocytes and NK cells were low. Most T lymphocytes exhibited the phenotype of memory /primed cells in both the CD4⁺ and CD8⁺ subpopulations. Two markers for recent activation, HLA-DR and interleukin-2 receptor (CD25) were not upregulated when compared with peripheral blood (PB) in the majority of CSF T lymphocytes. However, a fraction of T lymphocytes co-expressing the NK cell markers CD56 and/or CD16 showed a pronounced upregulation of HLA-DR in CSF as compared with PB. This study documents that the cellular composition of the normal CSF differs profoundly from PB regarding all major lymphocyte subpopulations. This has to be taken into account in studies addressing questions regarding cellular immune reactions in the central nervous system under pathological conditions.     

T lymphocyte subset abnormalities in peripheral blood from patients with the Guillain-Barré syndrome

T lymphocytes are probably of pathogenic importance in many autoimmune diseases. Recently, deviations of circulating T-helper (CD4⁺) subpopulations have been noticed. Blood samples from 12 patients with Guillain-Barré syndrome (GBS) were studied with flow cytometry during their disease to define circulating T cell populations. The proportion of T-helper cells (CD4⁺) was decreased (mean value 41±15%, P = 0.01) and the proportion of T cytotoxic/suppressor cells (CD8⁺) was increased (35±18%, P = 0.0006) as compared to the control group of healthy blood donors (47±8% and 26±7% respectively). The CD4⁺ population is divided into the helper/inducer (CD4⁺ CD29⁺) and suppressor/inducer (CD4⁺ CD45RA⁺) subsets. which normally are equally distributed (mean values in our control group were 45±15% and 44±15%, respectively). In patients with GBS, the helper/inducer (CD4⁺ CD29⁺) subset was increased (54±10%, P = 0.05) and the suppressor/inducer (CD4⁺ CD45RA⁺) subset was decreased (31±9, P = 0.005) compared to the controls. The proportion of activated HLA-DR-expressing T cells was increased (7±8%, P = 0.005) as compared to control (3±3%). The total proportions of T cells (CD2⁺), B cells (CD19⁺) and natural killer (NK) cells (CD56⁺) were similar in pateints and controls. The CD4⁺ and CD8⁺ populations, as well as the activated HLA-DR⁺ T cells, normalized during the disease course. The derivations within the CD4⁺ population also tended to normalize, but even at follow up after 6–33 (mean 23) months, some abnormalities remained. In conclusion, we confirm previous reports of T cell activation in peripheral blood from patients with GBS. A new finding is the derivation of T helper subpopulations with an increased helper/inducer (CD4⁺ CD29⁺) subset and a decreased suppressor/inducer (CD4⁺ CD45RA⁺) subset, which indicates a possible autoimmune character of GBS.     

Chronic reactive gliosis following regulatory T cell depletion during acute MCMV encephalitis

Long‐term, persistent central nervous system inflammation is commonly seen following brain infection. Using a murine model of viral encephalitis (murine cytomegalovirus, MCMV) we have previously shown that post‐encephalitic brains are maintained in an inflammatory state consisting of glial cell reactivity, retention of brain‐infiltrating tissue‐resident memory CD8⁺ T‐cells, and long‐term persistence of antibody‐producing cells of the B‐lineage. Here, we report that this neuroinflammation occurs concomitantly with accumulation and retention of immunosuppressive regulatory T‐cells (Tregs), and is exacerbated following their ablation. However, the extent to which these Tregs function to control neuroimmune activation following MCMV encephalitis is unknown. In this study, we used Foxp3‐diphtheria toxin receptor‐GFP (Foxp3‐DTR‐GFP) transgenic mice, which upon administration of low‐dose diphtheria toxin (DTx) results in the specific depletion of Tregs, to investigate their function. We found treatment with DTx during the acute phase of viral brain infection (0–4 dpi) resulted in depletion of Tregs from the brain, exacerbation of encephalitis (i.e., increased presence of CD4⁺ and CD8⁺ T‐cells), and chronic reactive phenotypes of resident glial cells (i.e., elevated MHC Class II as well as PD‐L1 levels, sustained microgliosis, and increased glial fibrillary acidic protein (GFAP) expression on astrocytes) versus untreated, infected animals. This chronic proinflammatory environment was associated with reduced cognitive performance in spatial learning and memory tasks (Barnes Maze) by convalescent animals. These data demonstrate that chronic glial cell activation, unremitting post‐encephalitic neuroinflammation, and its associated long‐term neurological sequelae in response to viral brain infection are modulated by the immunoregulatory properties of Tregs. GLIA 2015;63:1982–1996     

What’s new in chronic inflammatory demyelinating polyradiculoneuropathy in 2007–2008?

Abstract Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)–related research has made progress in the field of pathogenesis, genetics, and treatment. The number of circulating CD4⁺ CD25⁺ T‐regulatory cells was shown to be reduced in CIDP patients. Increased frequency of genotype GA13‐16 of the SH2D2A gene encoding for a T‐cell‐specific adapter protein in CIDP patients may result in a defective control and elimination of autoreactive T cells. IVIg treatment has been shown to increase numbers and function of peripheral CD4⁺ CD25⁺ T‐regulatory cell in a mouse model. These findings shed new light on the understanding of why peripheral tolerance is breached in CIDP patients and why the disease becomes chronic and adds another possible mechanism of action of intravenous immunoglobulin to the already long list. Long‐term effectiveness of IVIg has now been proven. Subcutaneous immunoglobulin could be an alternative for IVIg, but this has to be explored further in well‐designed trials. Autologous stem cell transplantation has been tried in refractory patients, but larger trials are necessary to assess safety and effect of this treatment.     

Synthesis of anti-acetylcholine receptor antibodies by CD5- B cells from peripheral blood of myasthenia gravis patients

An increased frequency of CD5⁺ B cells (or, according to a new nomenclature, B 1 cells) has been detected in the peripheral blood of a proportion of patients with myasthenia gravis (MG), as in some other autoimmune diseases. To elucidate the pathogenic significance of this B-cell subset in myasthenia gravis, mononuclear cells from the peripheral blood of six MG patients were separated into T and B lymphocytes by a magnetic cell separation procedure employing superparamagnetic microbeads (MACS). Subsequently, the B-cell fraction was depleted of CD5⁺ B cells in a second separation. The resulting purified CD5^– B-cell fraction was cultured alone or with the addition of autologous T cells. Anti-acetylcholine receptor (AChR) synthesis by CD5^– B cells in cultures with T cells was significantly increased by pokeweed mitogen (176 ±130 fmol/ml per week/2 × 10⁵ B cells) compared with unfractionated cells (75 ± 101) or CD5^– B cells alone (19 ± 4). These results demonstrate that in MG anti-AChR are synthesized, at least in part, by CD5^– B cells which are dependent on T cells. Although this does not exclude the existence of AChR-specific CD5⁺ B cells, it provides evidence against a pivotal role of this B-cell subset in anti-AChR synthesis.     

Determination of immune cells and expression of major histocompatibility complex class II antigen in encephalitic lesions of experimental Borna disease

Summary After intracerebral infection with Borna disease virus adult Lewis rats develop a virus-induced immunopathological reaction resulting in severe neurological symptoms and a non-purulent meningoencephalitis. The composition of inflammatory cells and major histocompatibility complex (MHC) class II antigen expression during the course of the infection was investigated using immunocytochemistry with a panel of monoclonal antibodies (mAb). Macrophages and lymphocytes of the T helper phenotype (CD4⁺) were dominant at all stages of infection, whereas T suppressor/cytotoxic lymphocytes (CD8⁺) were less frequent. B lymphocytes and plasma cells occurred mainly during later stages of the disease and marked parenchymal deposition of immunoglobulin developed. Beginning 10 days after infection massive expression of MHC class II antigen was noted up to the termination of experiments 70 days after infection. Besides lymphatic cells and macrophages, cells morphologically resembling microglia expressed this antigen. Furthermore, ependymal cells were found positive for MHC class II expression during infection whereas astrocytes remained negative. These findings are consistent with previous results which provide evidence for a delayed-type hypersensitivity reaction being operative in the pathogenesis of Borna disease.Supported by Deutsche Forschungsgemeinschaft     

Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4⁺ count was 117 and the HIV viral load >10⁴; imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4⁺ was 300 and HIV viral load <10³, but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8⁺ lymphocytes; CD4⁺ lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8⁺/CD4⁺ T cells, with massive infiltration of the cerebral parenchyma by CD8⁺ cytotoxic T lymphocytes in the absence of sufficient CD4⁺ response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.     

调节性T细胞及其免疫抑制机制

调节性T细胞是T细胞的一个重要亚型,对维持机体免疫动态平衡具有重要作用。调节性T细胞有两种类型:天然发生的调节性T细胞和诱导产生的调节性T细胞,前者在胸腺中发育;后者由外周幼稚CD4+T细胞衍生而来。调节性T细胞可利用多种机制抑制免疫应答,这些抑制机制可概括为4种基本的"作用模式":通过抑制性细胞因子发挥抑制作用,通过细胞溶解发挥抑制作用,通过代谢阻断发挥抑制作用,通过调节树突状细胞的成熟或功能发挥抑制作用。文中将天然调节性T细胞和诱导的调节性T细胞的发育以及调节性T细胞的免疫抑制机制做一综述,并简略介绍调节性T细胞在缺血性脑血管病中的作用。     

Dynamic changes in the systemic immune responses of spinal cord injury model mice

Intraspinal inflammatory and immune responses are considered to play central roles in the pathological development of spinal cord injury. This study aimed to decipher the dynamics of systemic immune responses, initiated by spinal cord injury. The spinal cord in mice was completely transected at T8. Changes in the in vivo inflammatory response, between the acute and subacute stages, were observed. A rapid decrease in C-reactive protein levels, circulating leukocytes and lymphocytes, spleen-derived CD4~+ interferon-γ+ T-helper cells, and inflammatory cytokines, and a marked increase in neutrophils, monocytes, and CD4~+CD25~+FOXP3~+ regulatory T-cells were observed during the acute phase. These systemic immune alterations were gradually restored to basal levels during the sub-acute phase. During the acute phase of spinal cord injury, systemic immune cells and factors showed significant inhibition; however, this inhibition was transient, and the indicators of these serious disorders gradually returned to baseline levels during the subacute phase. All experiments were performed in accordance with the institutional animal care guidelines, approved by the Institutional Animal Care and Use Committee of Experimental Animal Center of Drum Tower Hospital, China(approval No. 2019 AE01040) on June 25, 2019.     

T‐cells and macrophages peak weeks after experimental stroke: Spatial and temporal characteristics

The activities of the central and peripheral immune systems impact neurological outcome after ischemic stroke. However, studies investigating the temporal profile of leukocyte infiltration, especially T‐cell recruitment, are sparse. Our aim was to investigate leukocyte infiltration at different time points after experimental stroke in mice. Permanent middle cerebral artery occlusion was performed on 11 weeks old C57BL/6J mice, allowed to survive for 1, 3, 8, 14 or 28 days. In addition to infarct size measurements, detailed immunohistochemical analyses of T‐cell and macrophage influx were performed. A recently introduced F‐19 MR probe (V‐sense), designed to track macrophages, was furthermore tested. Fourteen and 28 days after permanent middle cerebral artery occlusion a significant increase in CD3⁺ T‐cells was found within the ipsilateral hemisphere compared to controls, especially within the infarct core and the corpus callosum. The number of CD68⁺ cells within the infarct core was significantly increased at days 8, 14 and 28. This temporal pattern was also seen in MRI. After experimental stroke within the infarcted cortex we found a delayed (day 14) infiltration of T‐cells and macrophages. Furthermore, our data show that T‐cells are present in higher numbers in the corpus callosum compared to the rest of the brain (except from the infarct core where they were highest).     

Regulatory T cells in ischemic stroke

The pathophysiological mechanisms of neuroinflammation, angiogenesis, and neuroplasticity are currently the hotspots of researches in ischemic stroke. Regulatory T cells (Tregs), a subset of T cells that control inflammatory and immune responses in the body, are closely related to the pathogenesis of ischemic stroke. They participate in the inflammatory response and neuroplasticity process of ischemic stroke by various mechanisms, such as secretion of anti-inflammatory factors, inhibition of pro-inflammatory factors, induction of cell lysis, production of the factors that promote neural regeneration, and modulation of microglial and macrophage polarization. However, it remains unclear whether Tregs play a beneficial or deleterious role in ischemic stroke and the effect of Tregs in different stages of ischemic stroke. Here, we discuss the dynamic changes of Tregs at various stages of experimental and clinical stroke, the potential mechanisms under Tregs in regulating stroke and the preclinical studies of Tregs-related treatments, in order to provide a reference for clinical treatment.