The Regulation of Apoptosis and Replicative Senescence in CD8+ T cells From Patients With Viral Infections

2000 ◽  
Vol 28 (1) ◽  
pp. A4-A4
Author(s):  
Arne N. Akbar
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Replicative Senescence ◽  
Viral Infections

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals IFN-Induced Attrition of CD8 T Cells in the Presence or Absence of Cognate Antigen during the Early Stages of Viral Infections

2006 ◽  
Vol 176 (7) ◽  
pp. 4284-4295 ◽  
Author(s):  
Kapil Bahl ◽  
Sung-Kwon Kim ◽  
Claudia Calcagno ◽  
Dario Ghersi ◽  
Roberto Puzone ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Early Stages ◽  
Cognate Antigen

scholarly journals Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Kingsley Gideon Kumashie ◽  
Marcin Cebula ◽  
Claudia Hagedorn ◽  
Florian Kreppel ◽  
Marina C. Pils ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Cell Formation ◽  
T Cell Response ◽  
Cellular Processes ◽  
Metabolic Functions ◽  
Cpg Oligonucleotide ◽  
Novel Approach

Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.

scholarly journals Metabolic Reprogramming in CD8+ T Cells During Acute Viral Infections

2020 ◽  
Vol 11 ◽  
Author(s):  
Shubhranshu S. Gupta ◽  
Jin Wang ◽  
Min Chen
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Metabolic Reprogramming

scholarly journals Protective to a T: The Role of T Cells during Zika Virus Infection

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 820 ◽  
Author(s):  
Ryan D. Pardy ◽  
Martin J. Richer
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Zika Virus ◽  
Viral Infections ◽  
Cross Reactivity ◽  
Negative Effects ◽  
Cell Responses ◽  
Recent Emergence ◽  
Human Infections

CD4 and CD8 T cells are an important part of the host’s capacity to defend itself against viral infections. During flavivirus infections, T cells have been implicated in both protective and pathogenic responses. Given the recent emergence of Zika virus (ZIKV) as a prominent global health threat, the question remains as to how T cells contribute to anti-ZIKV immunity. Furthermore, high homology between ZIKV and other, co-circulating flaviviruses opens the possibility of positive or negative effects of cross-reactivity due to pre-existing immunity. In this review, we will discuss the CD4 and CD8 T cell responses to ZIKV, and the lessons we have learned from both mouse and human infections. In addition, we will consider the possibility of whether T cells, in the context of flavivirus-naïve and flavivirus-immune subjects, play a role in promoting ZIKV pathogenesis during infection.

Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2711-2720 ◽  
Author(s):  
Jason M. Brenchley ◽  
Nitin J. Karandikar ◽  
Michael R. Betts ◽  
David R. Ambrozak ◽  
Brenna J. Hill ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Replicative Senescence ◽  
Interleukin 2 ◽  
Surface Expression ◽  
Antigen Stimulation ◽  
Chronic Antigenic Stimulation ◽  
Proliferative Ability

Virus-specific CD8+ T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8+ T cells to secrete cytokines and proliferate in response to HIV antigen stimulation. We find that a large proportion of HIV-specific CD8+ T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8+ T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8+ T cells, CD4+ T cells, and NK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57+ HIV-specific CD8+ T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8+ T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation.

High Expression of Granzymes and Perforin along with Increased T cell Cycling In Vivo Predicts the Development of Opportunistic Infections (OI) Following Unrelated Cord Blood Transplantation (UCBT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2238-2238
Author(s):  
Paul Szabolcs ◽  
Young-Ah Lee ◽  
Luciana Marti ◽  
Melissa Reese ◽  
Joanne Kurtzberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Opportunistic Infections ◽  
Cord Blood Transplantation ◽  
Ki 67 ◽  
Granzyme A ◽  
Blood Transplantation

Abstract Introduction: Unrelated umbilical cord blood transplantation (UUCBT) is a viable option for those who lack HLA-matched sibling donors. However, opportunistic infections (OI) occurring in the first 100 days, remain the major cause of morbidity and mortality. Viral infections are the primary cause of OI death. As previously shown, cord blood T cells have significantly less preformed effector molecules available intracellularly to kill virally infected cells via the perforin-granzyme pathway than adult PB T cells. Since several virally infected patients control their infections in the absence of specific antiviral therapy ( e.g adenoviral enteris, polyoma cystitis) we postulated that the T cell compartment of those UUCBT recipients who experience early viral infections maty upregulate expression of the perforin exocytosis pathway. In parallel the impact of viral infection on T cell turnover would also be appreciable. Here we report on 19 prospectively studied pediatric patients, all full donor chimera, following myeloablative therapy. Methods: On day +50 we determined by 4-color FACS the expression of intracellular Granzyme, A, B, along with perforin. To monitor T cell turnover proliferating cells were identified by monitoring for the KI-67 nuclear antigen. The expression of the antiapoptosis gene BCL-2 was similarly monitored in both CD4+ and CD8+ T cells. We analyzed their association with the development of de novo OI up to day +100 employing Student’s t-test. Results: Mean age of patients was 6.2 years. 10 of 19 patients developed OI (adenovirus x 4, CMV x 7, EBVx1, parainfluenza x 1) with 5/10 patients experiencing more than one viral infections simultaneously) at a median of 29 days after UUCBT. Of those with OI 6/10 died due to their infections while 8/9 without OI are alive at a median of 15.8 months after UUCBT with one death due to leukemic relapse. Table I presents the correlation between the tested parameters with the development of OI. Patients experiencing viral infections had significantly higher % of their T cells in particular CD8+ T cells equipped with effectors of cytotoxicity and were proliferating in higher percentage compared to those with no active infections. However, the anti-apoptotic protein BCL-2 expression was significantly lower in patients experiencing OI that may lead to their shorter life span and overall T cell lymphopenia observed in OI patietns that we have previously detected in a larger cohort of 102 patients (ASBMT 2004 abstract#48). Conclusion: Correlating with active viral infections significant maturation of cord blood T cells is evident as early as 50 days after UUCBT towards acquiring effector molecules of the perforin pathway. Enhanced T cell proliferation is counteracted by reduced expression of BCL-2 that may lead to the lymphopenia in patients with OI. Future strategies aiming to enhance the longevity of antiviral T cells may protect from death due to viral infections. Univariate analysis VARIABLE MEDIAN VALUE FOR PATIENTS WITH OI MEDIAN VALUE FOR PATIENTS WITHOUT OI t-Test p value % Granzyme A+ T cells 52% 9% 0.006 % Granzyme A+ CD8+ T cells 91% 47% <0.001 % Granzyme B+ T cells 36% 6% 0.036 % Granzyme B+ T cells 87% 39% <0.001 % Perforin+ T cells 38% 4% 0.009 % Perforin+ CD8+ T cells 61% 21% <0.001 % Ki-67+ T cells 27% 16% 0.0041 % Ki-67+ CD8+ T cells 35% 16% 0.0037 BCL-2 expression level (MFI) 87 117 0.028

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