Abstract 201: Changes In Inflammatory Response To Ischemic Stroke Across The Life Span

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Bharti Manwani ◽  
Fudong Liu ◽  
Lauren H Sansing ◽  
George Kuchel ◽  
Louise D McCullough
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Critical Role ◽  
T Cell Response ◽  
Aging Brain ◽  
Main Effect ◽  
Inflammatory Milieu ◽  
The Brain ◽  
Effect Of Age

Background/Purpose- Inflammation plays a critical role in the response to stroke, and post-ischemic inflammatory responses strongly contribute to the extent of ischemic brain injury. Although much is known about the post stroke inflammatory cascade in brain; the contribution of age to post ischemic inflammation has been understudied. Aging is a non-modifiable risk factor for stroke and is a critical determinant to stroke outcome. Since 75-89% of strokes occur in the elderly, it is important to characterize the differential effects of aging on the inflammatory response to stroke before translation of immunomodulatory therapeutic strategies into the clinic. Therefore, the objective of this study was to study the impact of aging on post s troke inflammatory milieu of the brain . Methods- Young(6 months), aging(15 months) and aged(22 months) male and female mice were subjected to 60 minutes of MCAO (n=5-6/ group). The ischemic hemisphere was subjected to mechanical and enzymatic digestion and then brain mononuclear cells were harvested at the 30%-60% interphase of percoll gradient. Cells were stained with fluorophore conjugated antibodies for CD45,CD3,CD11b and Gr1 and counted on LSRII cytometer(BD Biosciences). Results- Blood derived leukocytes(CD45high) increased in the brain in stroke(7133+−4514) vs. sham(1081+−279.9). We found a significant main effect of age, F(2,38)=5,p<0.05 and stroke, F(2,38)=19.5,p<0.01 in the percentage of T cells(CD45highCD3+). There was also a significant age by stroke interaction in the percentage of T cells, F(2,38)=0.58,p<0.05. In the CD45intermediateCD11b+ microglia population, we saw a significant main effect of stroke, F(1,38)=18.6,p<0.01 (sham 19199.2+−3439 vs. stroke 38365.4+−1111 ). Similarly, there was a significant main effect of stroke on CD45intermediate/CD11b+/Gr1+ microglia numbers, F(1,38)=12.6,p<0.01 . Conclusions- T cells, microglia and Gr1+ microglia numbers increase in the brain after an ischemic stroke. However, only the CD45hiCD3+T cells significantly increased in the aging brain after an ischemic insult in the two sexes. Microglia and Gr1+microglia did increase after stroke in both sexes, but there was no significant effect of age. Our study suggests that aging creates a differential inflammatory milieu in the brain after an ischemic event and that elderly mount a profound T cell response to stroke. Since most of our stroke patients are old, bench to clinic translation of stroke therapies needs to account for this heterogeneity in inflammatory response across different ages.

scholarly journals T Cell Response in Ischemic Stroke: From Mechanisms to Translational Insights

2021 ◽  
Vol 12 ◽  
Author(s):  
Dianhui Zhang ◽  
Jiaxin Ren ◽  
Yun Luo ◽  
Qianyan He ◽  
Ruoyu Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
T Cell ◽  
Time Windows ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Adaptive Immune System ◽  
T Cell Response ◽  
Beneficial Effects ◽  
The Brain

Ischemic stroke, caused by a sudden disruption of blood flow to the brain, is a leading cause of death and exerts a heavy burden on both patients and public health systems. Currently available treatments for ischemic stroke are very limited and are not feasible in many patients due to strict time windows required for their administration. Thus, novel treatment strategies are keenly required. T cells, which are part of the adaptive immune system, have gained more attention for its effects in ischemic stroke. Both preclinical and clinical studies have revealed the conflicting roles for T cells in post-stroke inflammation and as potential therapeutic targets. This review summarizes the mediators of T cell recruitment, as well as the temporal course of its infiltration through the blood-brain-barrier, choroid plexus, and meningeal pathways. Furthermore, we describe the mechanisms behind the deleterious and beneficial effects of T cells in the brain, in both antigen-dependent and antigen-independent manners, and finally we specifically focus on clinical and preclinical studies that have investigated T cells as potential therapeutic targets for ischemic stroke.

scholarly journals Glial Cell Expression of PD-L1

2019 ◽  
Vol 20 (7) ◽  
pp. 1677 ◽  
Author(s):  
Priyanka Chauhan ◽  
James Lokensgard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Pathogen Detection ◽  
Therapeutic Potential ◽  
Immune Checkpoint Blockade ◽  
Programmed Death ◽  
Cell Expression ◽  
Inflammatory Milieu ◽  
The Brain

The programmed death (PD)-1/PD-L1 pathway is a well-recognized negative immune checkpoint that results in functional inhibition of T-cells. Microglia, the brain-resident immune cells are vital for pathogen detection and initiation of neuroimmune responses. Moreover, microglial cells and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression. While T-cell suppressive responses within brain are undoubtedly beneficial to the host, preventing cytotoxic damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may simultaneously lead to deficiencies in viral clearance. An immune checkpoint blockade targeting the PD-1: PD-L1 (B7-H1; CD274) axis has revolutionized contemporary treatment for a variety of cancers. However, the therapeutic potential of PD1: PD-L1 blockade therapies targeting viral brain reservoirs remains to be determined. For these reasons, it is key to understand both the detrimental and protective functions of this signaling pathway within the brain. This review highlights how glial cells use PD-L1 expression to modulate T-cell effector function and limit detrimental bystander damage, while still retaining an effective defense of the brain.

scholarly journals Local Host Response to Chlamydial Urethral Infection in Male Guinea Pigs

2010 ◽  
Vol 78 (4) ◽  
pp. 1670-1681 ◽  
Author(s):  
Yin Wang ◽  
Uma Nagarajan ◽  
Leah Hennings ◽  
Anne K. Bowlin ◽  
Roger G. Rank
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Primary Infection ◽  
Host Response ◽  
Challenge Infection ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Genital Infection ◽  
Anamnestic Response ◽  
Necrosis Factor Alpha

ABSTRACT Very little is known about the host response to chlamydial genital infection in the male, particularly about the nature of the local response in the urethra. In this study, the pathological and immunologic responses to urethral infection of the male guinea pig with Chlamydia caviae (Chlamydophila caviae) were characterized both during a primary infection and following a challenge infection. A dose-response experiment found that the 50% infectious dose for male urethral infection was 78 inclusion-forming units. The histopathologic response was similar to that of the female, with an initial acute inflammatory response followed by a chronic inflammatory response and plasma cell infiltration. Production of IgG and IgA antibodies in local urethral secretions developed following infection, and levels of both increased in a typical anamnestic response following a challenge infection. CD4 and CD8 T cells, as well as B cells, were observed in the local site by flow cytometry, with a slightly increased number of CD8 cells. Following challenge infection, the dominant anamnestic response was solely in the B-cell compartment, with only a minimal number of T cells. The T-cell response was clearly a Th1 response, as judged by increased levels of gamma interferon (IFN-γ), interleukin-12 p40 (IL-12p40), and IL-2. The proinflammatory cytokines and chemokines IL-8, IL-1β, tumor necrosis factor alpha (TNF-α), CCL2 (monocyte chemoattractant protein 1 [MCP-1]), and CCL5 (RANTES) were elicited in the urethra following primary infection, but only CCL5 showed increased levels upon challenge. This study represents the first comprehensive analysis of the local immune response in the male urethra to a chlamydial genital infection.

scholarly journals IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

2018 ◽  
Author(s):  
Carleigh A. O’Brien ◽  
Samantha J. Batista ◽  
Katherine M. Still ◽  
Tajie H. Harris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Chronic Phase ◽  
T Cell Responses ◽  
T Cell Response ◽  
Neutrophil Recruitment ◽  
Cns Infection ◽  
Cell Responses ◽  
The Brain

AbstractControl of chronic CNS infection with the parasiteToxoplasma gondiirequires an ongoing T cell response in the brain. Immunosuppressive cytokines are also important for preventing lethal immunopathology during chronic infection. To explore the loss of suppressive cytokine exclusively during the chronic phase of infection we blocked IL-10 receptor (IL-10R). Blockade was associated with widespread changes in the inflammatory response, including increased antigen presenting cell (APC) activation, expansion of CD4+ T cells, and increased neutrophil recruitment to the brain, consistent with previous reports. We then sought to identify regulatory mechanisms contributing to IL-10 production, focusing on ICOS (inducible T cell costimulator), a molecule that promotes IL-10 production in many systems. Unexpectedly, ICOS-ligand (ICOSL) blockade led to a local expansion of effector T cells in the inflamed brain without affecting IL-10 production or APC activation. Instead, we found that ICOSL blockade led to changes in T cells associated with their proliferation and survival. Specifically, we observed increased expression of IL-2 associated signaling molecules, including CD25, STAT5 phosphorylation, Ki67, and Bcl-2 in T cells in the brain. Interestingly, increases in CD25 and Bcl-2 were not observed following IL-10R blockade. Also unlike IL-10R blockade, ICOSL blockade led to an expansion of both CD8+ and CD4+ T cells in the brain, with no expansion of peripheral T cell populations or neutrophil recruitment to the brain Overall, these results suggest that IL-10 and ICOS differentially regulate T cell responses in the brain during chronicT. gondiiinfection.

scholarly journals Gammadelta T Cells Are Required for CD8+ T Cell Response to Vaccinia Viral Infection

2021 ◽  
Author(s):  
Rui Dai ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cell Response ◽  
Critical Role ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Gammadelta T Cells

Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+ T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+ T cell response to VV infection. In this study, we showed that gammadelta T cells play an important role in promoting CD8+ T cell response to VV infection. We found that gammadelta T cells can directly present viral antigens in the context MHC-I for CD8+ T cell activation to VV in vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in gammadelta T cells is required for activation of gammadelta T cells and CD8+ T cells. These results illustrate a critical role for gammadelta T cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of gammadelta T cells.

Abstract WP96: The Role of T-Lymphocytes in Neuroregeneration After Cerebral Ischemia

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Kai Diederich ◽  
Antje Schmidt ◽  
Jan-Kolja Strecker ◽  
Wolf-Rüdiger Schäbitz ◽  
Jens Minnerup
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Adoptive Transfer ◽  
Critical Role ◽  
Chronic Phase ◽  
Cognitive Testing ◽  
Neurological Deficits ◽  
Ischemic Brain ◽  
Immunodeficient Mice

Introduction: Inflammation plays a critical role in the pathogenesis of ischemic stroke. The CNS responds to ischemic injury with an inflammatory process, characterized by an infiltration of inflammatory cells. Particularly T cells exhibit a great impact on early stroke outcome as recent studies showed that ablation of these cells decrease infarct size and improve neurological deficits in the acute phase after stroke. However, the role of T cells in the sub-acute and chronic phase after stroke is unknown. T cells are essential for effective neurogenesis and angiogenesis, mechanisms that are integral for successful regeneration after stroke. We assessed the hypothesis that T cells influence cellular mechanisms of post-ischemic neuroregeneration and consequently affect functional and structural recovery. Methods: 24 wild type (wt) and 11 RAG1 -/- mice were subjected to photothrombotic ischemia, a subset of 12 wt and 6 RAG1 -/- animals underwent training in motorized running wheels starting at day 3 following ischemia until the end of the experiment on day 28. Sensorimotor and cognitive testing was applied to quantify the recovery process. To label newly generated neurons, 5-Chloro-2′-deoxyuridine (CldU) and iododeoxyuridine (IdU) were administered at days 1 and 2 (CldU) and once weekly until day 28 (IdU) after ischemia. In a subsequent experiment, 17 RAG1 -/- mice were subjected to photothrombotic ischemia and underwent training, a subset of 10 animals received an adoptive transfer of T cells. Functional testing and cellular labeling were carried out in analogy to the first experiment. Results: Training improved recovery from sensorimotor and cognitive deficits following cortical ischemia in wt animals and increased the generation of new neurons in the ischemic brain. Rehabilitative training did not induce functional recovery in RAG1 -/- animals and had no effect on the generation of neurons. Adoptive transfer of T cells into the immunodeficient mice restored the ability for regeneration. Conclusion: T cells play an essential role in the functional and structural regeneration following ischemic brain injury. These results provide new clues on the complex mechanism by which immune cells impact different stages of the pathogenesis of ischemic stroke.

scholarly journals IL-4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites

2005 ◽  
Vol 202 (4) ◽  
pp. 551-560 ◽  
Author(s):  
Alexandre Morrot ◽  
Julius C.R. Hafalla ◽  
Ian A. Cockburn ◽  
Luzia H. Carvalho ◽  
Fidel Zavala
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Receptor Expression ◽  
Memory Cells ◽  
Malaria Parasites ◽  
Antiparasitic Activity ◽  
Memory Cd8 T Cells

IL-4 receptor (IL-4R)-deficient CD8+ T cells specific for the circumsporozoite protein of Plasmodium yoelii develop a severely impaired memory response after priming with parasites. Memory CD8+ T cells lacking the IL-4R are unable to establish a stable population residing in nonlymphoid organs, although they develop normally in lymphoid organs. Because memory cells from nonlymphoid organs disappear shortly after immunization, the protective antiparasitic activity of this T cell response also is lost. These results demonstrate that IL-4/IL-4R interactions on CD8+ T cells play a critical role in modulating the development and tissue distribution of memory cells induced by parasite immunization. They also indicate that memory cells residing in nonlymphoid tissues are critical for protective immunity against malaria parasites.

scholarly journals Priming of CD8+ T Cells during Central Nervous System Infection with a Murine Coronavirus Is Strain Dependent

2008 ◽  
Vol 82 (13) ◽  
pp. 6150-6160 ◽  
Author(s):  
Katherine C. MacNamara ◽  
Susan J. Bender ◽  
Ming Ming Chua ◽  
Richard Watson ◽  
Susan R. Weiss
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cns Infection ◽  
Cervical Lymph Nodes ◽  
T Cell Priming ◽  
The Brain

ABSTRACT Virus-specific CD8+ T cells are critical for protection against neurotropic coronaviruses; however, central nervous system (CNS) infection with the recombinant JHM (RJHM) strain of mouse hepatitis virus (MHV) elicits a weak CD8+ T-cell response in the brain and causes lethal encephalomyelitis. An adoptive transfer model was used to elucidate the kinetics of CD8+ T-cell priming during CNS infection with RJHM as well as with two MHV strains that induce a robust CD8+ T-cell response (RA59 and SJHM/RA59, a recombinant A59 virus expressing the JHM spike). While RA59 and SJHM/RA59 infections resulted in CD8+ T-cell priming within the first 2 days postinfection, RJHM infection did not lead to proliferation of naïve CD8+ T cells. While all three viruses replicated efficiently in the brain, only RA59 and SJHM/RA59 replicated to appreciable levels in the cervical lymph nodes (CLN), the site of T-cell priming during acute CNS infection. RJHM was unable to suppress the CD8+ T-cell response elicited by RA59 in mice simultaneously infected with both strains, suggesting that RJHM does not cause generalized immunosuppression. RJHM was also unable to elicit a secondary CD8+ T-cell response in the brain following peripheral immunization against a viral epitope. Notably, the weak CD8+ T-cell response elicited by RJHM was unique to CNS infection, since peripheral inoculation induced a robust CD8+ T-cell response in the spleen. These findings suggest that the failure of RJHM to prime a robust CD8+ T-cell response during CNS infection is likely due to its failure to replicate in the CLN.

scholarly journals The Dosage of the Derivative ofClostridium Ghonii(DCG) Spores Dictates Whether an IFNγ/IL-9 or a Strong IFNγResponse Is Elicited in TC-1 Tumour Bearing Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Guoying Ni ◽  
Yong Wang ◽  
David Good ◽  
Jianwei Yuan ◽  
Xuan Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
T Cell Response ◽  
Tumour Regression ◽  
Spleen Cells ◽  
Human Papillomavirus 16 ◽  
Tumour Bearing ◽  
Immune Mediated

Background. AnaerobicClostridialspores (CG) cause significant oncolysis in hypoxic tumour microenvironment and result in tumour regression in both animal models and clinical trials. The immune mediated response plays a critical role in the antitumour effect by the anaerobic spore treatment.Method. Human papillomavirus 16 E6/E7 transformed TC-1 tumour bearing mice were intravenously administered with low (1 × 108CFU/kg) or high dosage (3 × 108CFU/kg) of DerivativeClostridialspore (DCG).Results. Intravenous administration of the derivative ofClostridial ghonii(DCG) spores leads to both tumour and systemic inflammatory responses characterized by increased IFNγ/IL-9 secreting T cells in the spleen and the tumour. Low numbers of antigen specific T cells (<20/106spleen cells) in the spleen of the tumour bearing mice are also detected after intravenous DCG delivery. Interestingly, our results showed that a mixed IL-9/IFNγsecreting T cell response was induced when the tumour bearing mice received a low dose of DCG spore (1 × 108CFU/kg), while a strong IFNγresponse was elicited with a high dosage of DCG spore (3 × 108CFU/kg).Conclusion. The dosage of DCG spore will determine the types of the DCG induced immune responses.

scholarly journals Yellow Fever Virus Encephalitis: Properties of the Brain-Associated T-Cell Response during Virus Clearance in Normal and Gamma Interferon-Deficient Mice and Requirement for CD4+ Lymphocytes

2001 ◽  
Vol 75 (5) ◽  
pp. 2107-2118 ◽  
Author(s):  
Ting Liu ◽  
Thomas J. Chambers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Yellow Fever ◽  
Gamma Interferon ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Virus Clearance ◽  
Ifn Γ ◽  
The Brain

ABSTRACT Viral encephalitis caused by neuroadapted yellow fever 17D virus (PYF) was studied in parental and gamma interferon (IFN-γ)-deficient (IFN-γ knockout [GKO]) C57BL/6 mice. The T-cell responses which enter the brain during acute fatal encephalitis of nonimmunized mice, as well as nonfatal encephalitis of immunized mice, were characterized for relative proportions of CD4+ and CD8+cells, their proliferative responses, and antigen-specific expression of cytokines during stimulation in vitro. Unimmunized mice accumulated only low levels of T cells within the brain during fatal disease, whereas the brains of immunized mice contained higher levels of both T-cell subsets in response to challenge, with CD8+ cells increased relative to the CD4+ subset. The presence of T cells correlated with the time at which virus was cleared from the central nervous system in both parental and GKO mice. Lymphocytes isolated from the brains of challenged immunized mice failed to proliferate in vitro in response to T-cell mitogens or viral antigens; however, IFN-γ, interleukin 4 (IL-4), and, to a lesser extent, IL-2 were detectable after stimulation. The levels of IFN-γ, but not IL-2 or IL-4, were augmented in response to viral antigen, and this specificity was detectable in the CD4+ compartment. When tested for the ability to survive both immunization and challenge with PYF virus, GKO and CD8 knockout mice did not differ from parental mice (80 to 85% survival), although GKO mice exhibited a defect in virus clearance. In contrast, CD4 knockout and Igh-6 mice were unable to resist challenge. The data implicate antibody in conjunction with CD4+ lymphocytes bearing a Th1 phenotype as the critical factors involved in virus clearance in this model.

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