Functional Exhaustion Limits CD4<sup>+</sup>and CD8<sup>+</sup>T-Cell Responses to Congenital Cytomegalovirus Infection

Huygens, Ariane; Lecomte, Sandra; Tackoen, Marie; Olislagers, Véronique; Delmarcelle, Y; Burny, Wivine; Rysselberge, Michel Van; Liesnard, Corinne; Larsen, Martin; Appay, Victor; Donner, Cathérine; Marchant, Arnaud

doi:10.1093/infdis/jiv071

Cited by 54 publications

(54 citation statements)

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“…Interestingly, Jayasooriya et al have recently reported the case of one asymptomatic Epstein-Barr virus (EBV)-infected Gambian child who carried a virus load equivalent to that seen in acute infectious mononucleosis (AIM) patients but who lacked significant expansion of global T cell numbers despite substantial activation of EBV-specific CD8 ϩ T cells (29). In our study, PHIP mounted HCMV-specific T lymphocytes at frequencies comparable to those previously observed in primary HCMV-infected pregnant women and newborns (30)(31)(32)(33). We cannot exclude the hypothesis, suggested in AIM, of the development of heterologous immunity, where an existing response to an epitope encoded by a previously encountered pathogen cross-reacts with another from CMV, amplifying the pool of T cells responsive to CMV challenge and potentially inducing an exaggerated response.…”

Section: Discussionsupporting

confidence: 81%

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Riou

Bressollette-Bodin

Boutoille³

et al. 2017

J Virol

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Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMVseronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C ϩ NK cells, CD16 ϩ V␦2(Ϫ) ␥␦ T cells, and conventional HCMV-specific CD8 ϩ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

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Section: Discussionsupporting

confidence: 81%

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Riou

Bressollette-Bodin

Boutoille³

et al. 2017

J Virol

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“…However, it is not clear that CTLs primed in utero are fully functional. Following congenital HCMV infection, robust CTL responses resulting in perforin-dependent cytolysis and an adult-like memory differentiation phenotype have been described [53], but more recent data indicate that HCMV-specific CD8 + T cells have a markedly reduced capacity to produce effector cytokines when compared to adult cells [81]. As CD8 + T cells are critically dependent on the presence of CD4 + T cells at priming, it’s possible that deficiencies in CD4 + T cell helper function underlie the reduced effector and memory functions of CD8 + T cells primed in utero , but as this is unclear, future studies should test this possibility.…”

Section: Fetal and Neonatal Immune Systemsmentioning

confidence: 99%

Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity

Odorizzi

Feeney

2016

Trends in Molecular Medicine

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Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push towards malaria vaccines. KeywordsPlacental Malaria; Pregnancy-associated malaria; Fetal Immune System; Fetal Tolerance Global Impact of Pregnancy-Associated MalariaMalaria (see Glossary) remains one of the leading causes of morbidity and mortality worldwide, resulting in an estimated 500,000 deaths each year [1,2]. Pregnant women, infants and young children are the most vulnerable populations and account for the majority of infections. More than 125 million pregnancies occur annually in regions at risk for malaria transmission and one in four pregnant women in sub-Saharan Africa have evidence of malaria infection at parturition [1,2]. Moreover, pregnant women are at a greater risk for malaria infection relative to non-pregnant adults, experiencing higher levels of parasitemia and symptomatic disease [3,4]. Pregnancy-associated malaria, including placental malaria (PM), can have profound consequences on the developing fetus, leading to intrauterine growth retardation (IUGR), low birth weight (LBW), prematurity, miscarriage, and stillbirth [1,5].Corresponding author contact Information: margaret.feeney@ucsf.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptInfants and young children are highly susceptible to malaria during the first few years of life. In 2015, approximately 300,000 children under the age of five succumbed to malaria, with the highest mortality rates occurring in Africa [2]. Several epidemiological studies have found that the incidence of malaria during infancy and childhood is even higher among infants born to mothers with PM [6][7][8]. While this may partly due to the fact that infants of highly-exposed mothers are themselves at greater risk of environmental exposure, ...

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“…Immune based studies directly evaluating CMV‐specific T‐cell function have shown that CMV‐specific‐T cells that survive conditioning can protect against CMV from adult graft sources where mature T‐cells are either transferred in the graft or residual from CMV seropositive recipients . Conversely, limited T‐cell responses and T‐cell exhaustion have been shown in studies among UCBT and congenital CMV infection, respectively . While our study did not assess CMV‐specific T‐cells directly, we did analyze lower thresholds of mixed or full donor engraftment.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, McGoldrick et al have provided evidence that T‐cell responses to CMV after umbilical cord blood transplant (UCBT) were unable to control the virus due to insufficient in vivo expansion. Furthermore, Huygens et al reported that functional T‐cell exhaustion limited CMV‐specific T‐cell responses in newborns with congenital CMV infection; a model that would be more applicable to UCBT . Taken together, we hypothesize that mixed or full donor engraftment by day 30 after HSCT as measured by chimerism will be predictive of CMV reactivation in the following ways: In CMV D+ transplants, mixed donor engraftment will be predictive of freedom from CMV reactivation, and improved virus control in those with CMV reactivation compared to full donor engraftment.…”

Section: Introductionmentioning

confidence: 99%

Mixed vs full donor engraftment early after hematopoietic cell transplant: Impact on incidence and control of cytomegalovirus infection

Green

Shanley

Brunstein

et al. 2019

Transplant Infectious Dis

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Recovery of cytomegalovirus (CMV)‐specific immunity after hematopoietic cell transplantation (HCT) is essential in controlling CMV infection. We hypothesize that mixed donor engraftment as measured by chimerism at day 30 in CMV D(+) HCTs and full chimerism in CMV D(−) HCTs will be predictive of CMV reactivation. Prospectively collected data for 407 CMV R+ HCT recipients transplanted from 2006 to 2014 at the University of Minnesota were retrospectively analyzed. Full and mixed donor engraftment were defined as ≥95% or <95% donor cells at day 30, respectively. Source of engraftment determination included preferentially peripheral blood CD3 fraction, then myeloid cell fraction (CD15+), then bone marrow. In 407 CMV R+ subjects, 77% (n = 313) were CMV D(−) cells from umbilical cord blood (n = 209), peripheral blood (n = 58) or marrow (n = 46). Fifty three per cent received reduced intensity conditioning (RIC). At day +30, full donor engraftment was seen in 82% of myeloablative and 55% of RIC transplants. The cumulative incidence of CMV infection 1‐year after transplant was not different in patients with full (54%, n = 276) or mixed (53%, n = 131) donor engraftment. Control of CMV did not significantly differ among the two groups. In multiple regression analysis, there was no significant association between donor engraftment (mixed or full) and incidence or control of CMV.

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Functional Exhaustion Limits CD4⁺and CD8⁺T-Cell Responses to Congenital Cytomegalovirus Infection

Abstract: Functional exhaustion limits effector CD4(+) and CD8(+) T-lymphocyte responses to CMV during fetal life.

Cited by 54 publications

References 48 publications

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity

Mixed vs full donor engraftment early after hematopoietic cell transplant: Impact on incidence and control of cytomegalovirus infection

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Functional Exhaustion Limits CD4+and CD8+T-Cell Responses to Congenital Cytomegalovirus Infection

Abstract: Functional exhaustion limits effector CD4(+) and CD8(+) T-lymphocyte responses to CMV during fetal life.

Cited by 54 publications

References 48 publications

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity

Mixed vs full donor engraftment early after hematopoietic cell transplant: Impact on incidence and control of cytomegalovirus infection

Contact Info

Product

Resources

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Functional Exhaustion Limits CD4⁺and CD8⁺T-Cell Responses to Congenital Cytomegalovirus Infection