scholarly journals Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

2003 ◽  
Vol 77 (8) ◽  
pp. 4911-4927 ◽  
Author(s):  
E. John Wherry ◽  
Joseph N. Blattman ◽  
Kaja Murali-Krishna ◽  
Robbert van der Most ◽  
Rafi Ahmed
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tissue Distribution ◽  
Functional Impairment ◽  
Chronic Infection ◽  
Cd8 T Cell ◽  
Effector Functions ◽  
Cell Responses ◽  
Functional Exhaustion ◽  
Cell Effector

ABSTRACT Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.

Obesity results in higher PD-1-mediated T-cell suppression but greater T-cell effector functions following blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 65-65 ◽  
Author(s):  
Robert J. Canter ◽  
Ethan Aguilar ◽  
Ziming Wang ◽  
Catherine Le ◽  
Lam Khuat ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Murine Cytomegalovirus ◽  
Obese Mice ◽  
Effector Functions ◽  
Cell Responses ◽  
The Central Nervous System ◽  
The Impact ◽  
Cell Effector

65 Background: Obesity is increasingly prevalent and viewed as a critical co-factor in many pathologic conditions due to metabolic, inflammatory and immune perturbations. We performed a multi-species evaluation of the impact of obesity T cell effector functions and markers of immune exhaustion. Methods: We examined the impact of obesity on PD-1 and T cell-mediated responses across different pre-clinical models (tumor, infection, and autoimmune encephalomyelitis [EAE]) and species (mouse, dog, non-human primate, and human). Results: CD4 and CD8 T cells from obese mice, dogs, non-human primates and humans displayed increases in memory T cells and PD-1 expression, as well as impaired proliferative responses compared to lean controls, indicating a greater degree of T cell exhaustion at baseline. Following immunization with myelin oligodendrocyte glycoprotein, obese mice were resistant to induction of EAE, correlating with reduced antigen-specific CD4 T cells in the central nervous system. Administration of anti-PD-1 resulted in restoration of EAE and increased antigen-specific T cell numbers in obese mice. Tumors in obese mice exhibited accelerated growth compared to lean mice, and T cells displayed higher PD-1 expression correlating with RNAseq/molecular signatures of exhaustion compared to tumor-bearing lean mice. PD-1 blockade resulted in marked anti-tumor effects only in obese mice, and not lean. Impaired viral resistance to murine cytomegalovirus (MCMV) resulted was seen in obese mice, associated with increased PD-1/PD-L1 expression, which was reversible by PD-1/PD-L1 blockade. Conclusions: Obesity results in an increase in PD-1/PD-L1 expression and inhibition of T cell responses across species, and blockade not only reverses this inhibition but also leads to markedly augmented T cell effector responses compared to lean counterparts where no effects were observed. These results highlight how the immune system has evolved to control T cell responses using checkpoints contingent on dynamic host conditions and have translational relevance for predicting both efficacy and toxicity in clinical immuno-oncology.

scholarly journals Type 1 diabetes progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T-cell effector functions

2020 ◽  
Vol 2 (2) ◽  
pp. 142-152 ◽  
Author(s):  
Giuseppe Terrazzano ◽  
Sara Bruzzaniti ◽  
Valentina Rubino ◽  
Marianna Santopaolo ◽  
Anna Teresa Palatucci ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cell ◽  
Effector Functions ◽  
Diabetes Progression ◽  
Cell Effector

scholarly journals Defining Kinetic Properties of HIV-Specific CD8+ T-cell Responses in Acute Infection

2019 ◽  
Author(s):  
Yiding Yang ◽  
Vitaly V. Ganusov
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chronic Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Average Viral Load

Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

scholarly journals Defining Kinetic Properties of HIV-Specific CD8+ T-Cell Responses in Acute Infection

2019 ◽  
Vol 7 (3) ◽  
pp. 69 ◽  
Author(s):  
Yiding Yang ◽  
Vitaly Ganusov
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chronic Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Average Viral Load

Multiple lines of evidence indicate that CD8 + T cells are important in the control of HIV-1 (HIV) replication. However, CD8 + T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8 + T-cell responses induced during HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8 + T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8 + T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8 + T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8 + T cells in the chronic infection. The breadth of HIV-specific CD8 + T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8 + T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8 + T-cell responses and the presence of intra- and interclonal competition between multiple CD8 + T-cell responses; such competition may limit the magnitude of CD8 + T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8 + T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

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 Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

2006 ◽  
Vol 81 (2) ◽  
pp. 934-944 ◽  
Author(s):  
Markus Cornberg ◽  
Brian S. Sheridan ◽  
Frances M. Saccoccio ◽  
Michael A. Brehm ◽  
Liisa K. Selin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Molecular Mimicry ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

scholarly journals Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

PLoS ONE ◽  
2008 ◽  
Vol 3 (10) ◽  
pp. e3577 ◽  
Author(s):  
J. William Critchfield ◽  
Delandy H. Young ◽  
Timothy L. Hayes ◽  
Jerome V. Braun ◽  
Juan C. Garcia ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Infection ◽  
Clinical Status ◽  
Rectal Mucosa ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Hiv 1

scholarly journals Mitochondrial Dysfunction Associates With Acute T Lymphocytopenia and Impaired Functionality in COVID-19 Patients

2022 ◽  
Vol 12 ◽  
Author(s):  
Yufei Mo ◽  
Kelvin Kai-Wang To ◽  
Runhong Zhou ◽  
Li Liu ◽  
Tianyu Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mitochondrial Dysfunction ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
Cell Loss ◽  
Cd8 T Cell ◽  
Underlying Mechanism ◽  
T Cell Subsets ◽  
Effector Memory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

Sign in / Sign up

Export Citation Format

Share Document