T cell exhaustion during persistent viral infections

Kahan, Shannon M.; Wherry, E. John; Zajac, Allan

doi:10.1016/j.virol.2014.12.033

Cited by 263 publications

(257 citation statements)

References 222 publications

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“…DV can inhibit IFN-␣ production (42) but possibly not IFN-␥ production, although other flaviviruses, such as West Nile virus, do inhibit the production of the two interferon types (43). However, the continuous activation of PBMCs during dengue infection may force the cells to a state of exhaustion (44,45). In addition, an inhibitory effect of interleukin-10 (IL-10), a cytokine expressed during the infection, on the secretion of other cytokines should also be considered (46).…”

Section: Discussionmentioning

confidence: 99%

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

Perdomo‐Celis

Salgado

Castañeda

et al. 2016

Clin Vaccine Immunol

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bCryopreserved peripheral blood mononuclear cells (PBMCs) are widely used in studies of dengue. In this disease, elevated frequency of apoptotic PBMCs has been described, and molecules such as soluble tumor necrosis factor (TNF)-related apoptosisinducing ligands (sTRAIL) are involved. This effect of dengue may affect the efficiency of PBMC cryopreservation. Here, we evaluate the viability (trypan blue dye exclusion and amine-reactive dye staining) and functionality (frequency of gamma interferon [IFN-␥]-producing T cells after polyclonal stimulation) of fresh and cryopreserved PBMCs from children with dengue (in acute and convalescence phases), children with other febrile illnesses, and healthy children as controls. Plasma sTRAIL levels were also evaluated. The frequencies of nonviable PBMCs detected by the two viability assays were positively correlated (r ‫؍‬ 0.74; P < 0.0001). Cryopreservation particularly affected the PBMCs of children with dengue, who had a higher frequency of nonviable cells than healthy children and children with other febrile illnesses (P < 0.02), and PBMC viability levels were restored in the convalescent phase. In the acute phase, an increased frequency of CD3 ؉ CD8 ؉ amine-positive cells was found before cryopreservation (P ‫؍‬ 0.01). Except for B cells in the acute phase, cryopreservation usually did not affect the relative frequencies of viable PBMC subpopulations. Dengue infection reduced the frequency of IFN-␥-producing CD3؉ cells after stimulation compared with healthy controls and convalescent-phase patients (P < 0.003), and plasma sTRAIL correlated with this decreased frequency in dengue (rho ‫؍‬ ؊0.56; P ‫؍‬ 0.01). Natural dengue infection in children can affect the viability and functionality of cryopreserved PBMCs. Cryopreservation is the maintenance of cells and biological tissues at low temperatures and is based on the use of various media or solutions that form hydrogen bonds with water molecules, preventing cellular damage. The low temperatures allow the cells to enter a quiescent state in which cellular functions are suspended without affecting their intrinsic characteristics (1). Peripheral blood mononuclear cells (PBMCs) are frequently cryopreserved for use in transplants or immunological studies (2, 3). However, the cryopreservation process may affect viability, phenotype, and cellular functionality due to factors such as inadequate temperatures, the freezing protocol used, the expertise of the personnel, and freezing time (4, 5). The disease of the individual from whom the PBMCs come also affects cryopreservation. For example, PBMCs from subjects infected with human immunodeficiency virus (HIV) presented reduced viability after cryopreservation, possibly due to the increased numbers of apoptotic cells circulating during the course of the disease (6). Similar findings have been found in the acute phases of diseases, such as visceral leishmaniasis (7). Particularly for HIV, great efforts have been undertaken to optimize the evaluation and comparability of immune tests...

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Section: Discussionmentioning

confidence: 99%

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

Perdomo‐Celis

Salgado

Castañeda

et al. 2016

Clin Vaccine Immunol

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“…That is, exhausted T cells come from cells that initially developed an effector function but then gradually lose it because of continuous stimulation of the T cell receptor (TCR) from the persistent antigen helping to build peripheral tolerance as well as to modulate immune responses [111,112]. As such, exhausted T cells present in patients having autoimmune disorders correlate with positive prognoses [113]. However, in cancers, exhausted T cells may block tumor clearance, thereby contributing to immune escape [114,115].…”

Section: T Cell Exhaustionmentioning

confidence: 99%

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

Torres¹,

López-Casado²,

León³

et al. 2017

Physiology and Pathology of Immunology

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The immune system is responsible for the defense of the organism. It controls what is introduced into it and identifies it as self from non-self. The defensive mechanisms activated by the immune system are directed against pathological microbes and toxic or allergenic proteins, and it must avoid responses that produce excessive damage of self-tissues, inducing tolerance to avoid autoimmunity and other immunopathologies. Regulatory Tcells play an essential role in these active processes, using several distinct suppressive mechanisms. The immune dysregulatory diseases result from defects affecting regulatory T cell development and/or function, including the impact of essential genes mutations for Tregulatory cell functions and the associated autoimmune syndromes.

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“…Our findings indicate that the drop in virus load after pregnancy was associated with enhanced T-cell immunity, a favorable IFNL3 genotype, and high HLA-DPB1 expression. High antigen loads contribute to T-cell exhaustion (37). It is therefore possible that reduced virus replication after pregnancy caused or contributed to reversal of T-cell exhaustion.…”

Section: Resultsmentioning

confidence: 99%

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery

Honegger

Tedesco

Kohout

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log 10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3-and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.hepatitis C virus | pregnancy | T-cell | IFNL3 | HLA-DPB1

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T cell exhaustion during persistent viral infections

Cited by 263 publications

References 222 publications

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery

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