Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 3/2015

01-04-2015 | Original Research

Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

Authors: Laura Gibson, Constance M. Barysauskas, Margaret McManus, Sheryl Dooley, Daniele Lilleri, Donna Fisher, Tumul Srivastava, Don J. Diamond, Katherine Luzuriaga

Published in: Journal of Clinical Immunology | Issue 3/2015

Login to get access

Abstract

Purpose

CMV infection remains a priority for vaccine development. Vaccination of infants could modify congenital infection and provide lifetime immunity. Properties of CMV-specific T cells associated with control of viral replication in early life have not been fully defined.

Methods

CMV-specific CD4 and CD8 T cell responses were investigated in infants with congenital CMV infection and compared to adults with primary or chronic infection. PBMC were stimulated with UL83 (pp65) or UL122 (IE-2) peptide pools then stained with antibodies to markers of T cell subset (CD4 or CD8), phenotype (CD45RA, CCR7), or function (MIP1β, CD107, IFNγ, IL2) for flow cytometry analysis.

Results

Detection of CMV pp65-specific CD4 T cells was less common in infants than adults. Responder cells were primarily effector memory (EM, CD45RA-CCR7-) in adults, but mixed memory subsets in infants. Detection of CMV pp65-specific CD8 T cells did not differ between the groups, but infants had lower frequencies of total responding cells and of MIP1β- or CD107-expressing cells. Responder cells were EM or effector memory RA (CD45RA + CCR7-) in all groups. Polyfunctional T cells were less commonly detected in infants than adults. Responses to IE-2 were detected in adults but not infants. All infants had detectable circulating CMV DNA at initial study (versus 60 % of adults with primary infection) despite longer duration of CMV infection.

Conclusions

Reduced frequencies and altered functional profile of CMV-specific CD4 and CD8 T cell responses were detected in infants compared to adults, and were associated with persistent CMV DNA in peripheral blood.
Literature
1.
2.
Cannon MJ. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol. 2009;46 Suppl 4:S6–10.CrossRefPubMed
3.
Adler SP. Cytomegalovirus and child day care. Evidence for an increased infection rate among day-care workers. N Engl J Med. 1989;321(19):1290–6.CrossRefPubMed
4.
Adler SP. Cytomegalovirus and child day care: risk factors for maternal infection. Pediatr Infect Dis J. 1991;10(8):590–4.CrossRefPubMed
5.
Noyola DE, Demmler GJ, Williamson WD, Griesser C, Sellers S, Llorente A, et al. Cytomegalovirus urinary excretion and long term outcome in children with congenital cytomegalovirus infection. Congenital CMV Longitudinal Study Group. Pediatr Infect Dis J. 2000;19(6):505–10.CrossRefPubMed
6.
Krause PR, Bialek SR, Boppana SB, Griffiths PD, Laughlin CA, Ljungman P, et al. Priorities for CMV vaccine development. Vaccine. 2013.
7.
Prendergast AJ, Klenerman P, Goulder PJ. The impact of differential antiviral immunity in children and adults. Nat Rev Immunol. 2012;12(9):636–48.CrossRefPubMed
8.
Lanzieri TM, Bialek SR, Ortega-Sanchez IR, Gambhir M. Modeling the potential impact of vaccination on the epidemiology of congenital cytomegalovirus infection. Vaccine. 2014.
9.
Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012;12(4):290–9.CrossRefPubMed
10.
Heineman TC, Schleiss M, Bernstein DI, Spaete RR, Yan L, Duke G, et al. A phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimeric vaccines. J Infect Dis. 2006;193(10):1350–60.CrossRefPubMed
11.
12.
Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E, Flechsig C, et al. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog. 2014;10(11):e1004524.CrossRefPubMedCentralPubMed
13.
Zhong J, Khanna R. Delineating the role of CD4+ T cells in the activation of human cytomegalovirus-specific immune responses following immunization with Ad-gBCMVpoly vaccine: implications for vaccination of immunocompromised individuals. J Gen Virol. 2010;91(Pt 12):2994–3001.CrossRefPubMed
14.
Renzette N, Gibson L, Jensen JD, Kowalik TF. Human cytomegalovirus intrahost evolution-a new avenue for understanding and controlling herpesvirus infections. Curr Opin Virol. 2014;8:109–15.CrossRefPubMed
15.
La Rosa C, Diamond DJ. The immune response to human CMV. Futur Virol. 2012;7(3):279–93.CrossRef
16.
Bohm V, Podlech J, Thomas D, Deegen P, Pahl-Seibert MF, Lemmermann NA, et al. Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy. Med Microbiol Immunol. 2008;197(2):135–44.CrossRefPubMed
17.
Jeitziner SM, Walton SM, Torti N, Oxenius A. Adoptive transfer of cytomegalovirus-specific effector CD4+ T cells provides antiviral protection from murine CMV infection. Eur J Immunol. 2013;43(11):2886–95.CrossRefPubMed
18.
Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev G, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med. 2005;201(7):1031–6.CrossRefPubMedCentralPubMed
19.
Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003;101(7):2686–92.CrossRefPubMed
20.
Sacre K, Carcelain G, Cassoux N, Fillet AM, Costagliola D, Vittecoq D, et al. Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease. J Exp Med. 2005;201(12):1999–2010.CrossRefPubMedCentralPubMed
21.
Luo XH, Huang XJ, Liu KY, Xu LP, Liu DH. Protective immunity transferred by infusion of cytomegalovirus-specific CD8(+) T cells within donor grafts: its associations with cytomegalovirus reactivation following unmanipulated allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16(7):994–1004.CrossRefPubMed
22.
Chen SF, Tu WW, Sharp MA, Tongson EC, He XS, Greenberg HB, et al. Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood. J Infect Dis. 2004;189(9):1619–27.CrossRefPubMed
23.
Gibson L, Dooley S, Trzmielina S, Somasundaran M, Fisher D, Revello MG, et al. Cytomegalovirus (CMV) IE1- and pp 65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants. J Infect Dis. 2007;195(12):1789–98.CrossRefPubMed
24.
Gibson L, Piccinini G, Lilleri D, Revello MG, Wang Z, Markel S, et al. Human cytomegalovirus proteins pp 65 and immediate early protein 1 are common targets for CD8+ T cell responses in children with congenital or postnatal human cytomegalovirus infection. J Immunol. 2004;172(4):2256–64.CrossRefPubMed
25.
Marchant A, Appay V, Van Der Sande M, Dulphy N, Liesnard C, Kidd M, et al. Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest. 2003;111(11):1747–55.CrossRefPubMedCentralPubMed
26.
Miles DJ, Sande M, Kaye S, Crozier S, Ojuola O, Palmero MS, et al. CD4(+) T cell responses to cytomegalovirus in early life: a prospective birth cohort study. J Infect Dis. 2008;197(5):658–62.CrossRefPubMed
27.
Tu W, Chen S, Sharp M, Dekker C, Manganello AM, Tongson EC, et al. Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children. J Immunol. 2004;172(5):3260–7.CrossRefPubMed
28.
Lidehall AK, Engman ML, Sund F, Malm G, Lewensohn-Fuchs I, Ewald U, et al. Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children. Scand J Immunol. 2013;77(2):135–43.CrossRefPubMed
29.
Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who’s who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol. 2013;43(11):2797–809.CrossRefPubMed
30.
Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006;107(12):4781–9.CrossRefPubMedCentralPubMed
31.
Nebbia G, Mattes FM, Smith C, Hainsworth E, Kopycinski J, Burroughs A, et al. Polyfunctional cytomegalovirus-specific CD4+ and pp 65 CD8+ T cells protect against high-level replication after liver transplantation. Am J Transplant. 2008;8(12):2590–9.CrossRefPubMed
32.
Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L, et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood. 2009;113(25):6465–76.CrossRefPubMedCentralPubMed
33.
Bernstein DI, Reap EA, Katen K, Watson A, Smith K, Norberg P, et al. Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine. 2009;28(2):484–93.CrossRefPubMed
34.
Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med. 2007;204(6):1405–16.CrossRefPubMedCentralPubMed
35.
Soares AP, Scriba TJ, Joseph S, Harbacheuski R, Murray RA, Gelderbloem SJ, et al. Bacillus Calmette-Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol. 2008;180(5):3569–77.CrossRefPubMedCentralPubMed
36.
Schmueck M, Fischer AM, Hammoud B, Brestrich G, Fuehrer H, Luu SH, et al. Preferential expansion of human virus-specific multifunctional central memory T cells by partial targeting of the IL-2 receptor signaling pathway: the key role of CD4+ T cells. J Immunol. 2012;188(10):5189–98.CrossRefPubMed
37.
Gerna G, Revello MG, Percivalle E, Zavattoni M, Parea M, Battaglia M. Quantification of human cytomegalovirus viremia by using monoclonal antibodies to different viral proteins. J Clin Microbiol. 1990;28(12):2681–8.PubMedCentralPubMed
38.
Revello MG, Zavattoni M, Baldanti F, Sarasini A, Paolucci S, Gerna G. Diagnostic and prognostic value of human cytomegalovirus load and IgM antibody in blood of congenitally infected newborns. J Clin Virol. 1999;14(1):57–66.CrossRefPubMed
39.
Revello MG, Zavattoni M, Sarasini A, Percivalle E, Simoncini L, Gerna G. Human cytomegalovirus in blood of immunocompetent persons during primary infection: prognostic implications for pregnancy. J Infect Dis. 1998;177(5):1170–5.CrossRefPubMed
40.
Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002;15(4):680–715.CrossRefPubMedCentralPubMed
41.
Revello MG, Lilleri D, Zavattoni M, Furione M, Genini E, Comolli G, et al. Lymphoproliferative response in primary human cytomegalovirus (HCMV) infection is delayed in HCMV transmitter mothers. J Infect Dis. 2006;193(2):269–76.CrossRefPubMed
42.
Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA. 2011;305(6):576–84.CrossRefPubMed
43.
Johnson DC, McFarland EJ, Muresan P, Fenton T, McNamara J, Read JS, et al. Safety and immunogenicity of an HIV-1 recombinant canarypox vaccine in newborns and infants of HIV-1-infected women. J Infect Dis. 2005;192(12):2129–33.CrossRefPubMed
44.
Wang Z, Zhou W, Srivastava T, La Rosa C, Mandarino A, Forman SJ, et al. A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. Virology. 2008;377(2):379–90.CrossRefPubMedCentralPubMed
45.
Revello MG, Sarasini A, Zavattoni M, Baldanti F, Gerna G. Improved prenatal diagnosis of congenital human cytomegalovirus infection by a modified nested polymerase chain reaction. J Med Virol. 1998;56(1):99–103.CrossRefPubMed
46.
Gerna G, Vitulo P, Rovida F, Lilleri D, Pellegrini C, Oggionni T, et al. Impact of human metapneumovirus and human cytomegalovirus versus other respiratory viruses on the lower respiratory tract infections of lung transplant recipients. J Med Virol. 2006;78(3):408–16.CrossRefPubMed
47.
48.
Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. J Clin Virol. 2008;41(3):192–7.CrossRefPubMed
49.
Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85.CrossRefPubMedCentralPubMed
50.
Griffiths P, Plotkin S, Mocarski E, Pass R, Schleiss M, Krause P, et al. Desirability and feasibility of a vaccine against cytomegalovirus. Vaccine. 2013;31 Suppl 2:B197–203.CrossRefPubMed
51.
Azevedo RS, Amaku M. Modelling immunization strategies with cytomegalovirus vaccine candidates. Epidemiol Infect. 2011;139(12):1818–26.CrossRefPubMed
52.
Mansoor N, Abel B, Scriba TJ, Hughes J, de Kock M, Tameris M, et al. Significantly skewed memory CD8+ T cell subsets in HIV-1 infected infants during the first year of life. Clin Immunol. 2009;130(3):280–9.CrossRefPubMedCentralPubMed
53.
Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014;35(2):51–60.PubMedCentralPubMed
54.
55.
Bronke C, Jansen CA, Westerlaken GH, De Cuyper IM, Miedema F, Tesselaar K, et al. Shift of CMV-specific CD4+ T-cells to the highly differentiated CD45RO-CD27- phenotype parallels loss of proliferative capacity and precedes progression to HIV-related CMV end-organ disease. Clin Immunol. 2007;124(2):190–9.CrossRefPubMed
56.
Pourgheysari B, Piper KP, McLarnon A, Arrazi J, Bruton R, Clark F, et al. Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant. 2009;43(11):853–61.CrossRefPubMed
57.
Lilleri D, Fornara C, Revello MG, Gerna G. Human cytomegalovirus-specific memory CD8+ and CD4+ T cell differentiation after primary infection. J Infect Dis. 2008;198(4):536–43.CrossRefPubMed
58.
Casazza JP, Betts MR, Price DA, Precopio ML, Ruff LE, Brenchley JM, et al. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med. 2006;203(13):2865–77.CrossRefPubMedCentralPubMed
59.
Gehrz RC, Marker SC, Knorr SO, Kalis JM, Balfour Jr HH. Specific cell-mediated immune defect in active cytomegalovirus infection of young children and their mothers. Lancet. 1977;2(8043):844–7.CrossRefPubMed
60.
Pass RF, Stagno S, Britt WJ, Alford CA. Specific cell-mediated immunity and the natural history of congenital infection with cytomegalovirus. J Infect Dis. 1983;148(6):953–61.CrossRefPubMed
61.
Starr SE, Tolpin MD, Friedman HM, Paucker K, Plotkin SA. Impaired cellular immunity to cytomegalovirus in congenitally infected children and their mothers. J Infect Dis. 1979;140(4):500–5.CrossRefPubMed
62.
Pass RF, Dworsky ME, Whitley RJ, August AM, Stagno S, Alford Jr CA. Specific lymphocyte blastogenic responses in children with cytomegalovirus and herpes simplex virus infections acquired early in infancy. Infect Immun. 1981;34(1):166–70.PubMedCentralPubMed
63.
Kim TK, St John LS, Wieder ED, Khalili J, Ma Q, Komanduri KV. Human late memory CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production without IL-2 production. J Immunol. 2009;183(10):6167–74.CrossRefPubMed
64.
Riou C, Treurnicht F, Abrahams MR, Mlisana K, Liu MK, Goonetilleke N, et al. Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for cytomegalovirus-specific CD8+ T cells. J Immunol. 2012;189(8):3838–47.CrossRefPubMedCentralPubMed
65.
Thobakgale CF, Streeck H, Mkhwanazi N, Mncube Z, Maphumulo L, Chonco F, et al. Short communication: CD8(+) T cell polyfunctionality profiles in progressive and nonprogressive pediatric HIV type 1 infection. AIDS Res Hum Retroviruses. 2011;27(9):1005–12.CrossRefPubMedCentralPubMed
66.
Huang S, Dunkley-Thompson J, Tang Y, Macklin EA, Steel-Duncan J, Singh-Minott I, et al. Deficiency of HIV-Gag-specific T cells in early childhood correlates with poor viral containment. J Immunol. 2008;181(11):8103–11.CrossRefPubMedCentralPubMed
67.
Ritz N, Strach M, Yau C, Dutta B, Tebruegge M, Connell TG, et al. A comparative analysis of polyfunctional T cells and secreted cytokines induced by Bacille Calmette-Guerin immunisation in children and adults. PLoS One. 2012;7(7):e37535.CrossRefPubMedCentralPubMed
68.
Cannon MJ, Hyde TB, Schmid DS. Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection. Rev Med Virol. 2011;21(4):240–55.CrossRefPubMed
69.
Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16–25.CrossRefPubMed
70.
McCarron MJ, Reen DJ. Neonatal CD8+ T-cell differentiation is dependent on interleukin-12. Hum Immunol. 2010;71(12):1172–9.CrossRefPubMed
71.
72.
Sandberg JK, Fast NM, Jordan KA, Furlan SN, Barbour JD, Fennelly G, et al. HIV-specific CD8+ T cell function in children with vertically acquired HIV-1 infection is critically influenced by age and the state of the CD4+ T cell compartment. J Immunol. 2003;170(8):4403–10.CrossRefPubMed
73.
Antoine P, Olislagers V, Huygens A, Lecomte S, Liesnard C, Donner C, et al. Functional exhaustion of CD4+ T lymphocytes during primary cytomegalovirus infection. J Immunol. 2012;189(5):2665–72.CrossRefPubMed
74.
Slavuljica I, Kvestak D, Huszthy PC, Kosmac K, Britt WJ, Jonjic S. Immunobiology of congenital cytomegalovirus infection of the central nervous system-the murine cytomegalovirus model. Cell Mol Immunol. 2014.
75.
Gabrielli L, Bonasoni MP, Santini D, Piccirilli G, Chiereghin A, Petrisli E, et al. Congenital cytomegalovirus infection: patterns of fetal brain damage. Clin Microbiol Infect. 2012;18(10):E419–27.CrossRefPubMed
76.
Khan N, Bruton R, Taylor GS, Cobbold M, Jones TR, Rickinson AB, et al. Identification of cytomegalovirus-specific cytotoxic T lymphocytes in vitro is greatly enhanced by the use of recombinant virus lacking the US2 to US11 region or modified vaccinia virus Ankara expressing individual viral genes. J Virol. 2005;79(5):2869–79.CrossRefPubMedCentralPubMed
Metadata
Title
Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection
Authors
Laura Gibson
Constance M. Barysauskas
Margaret McManus
Sheryl Dooley
Daniele Lilleri
Donna Fisher
Tumul Srivastava
Don J. Diamond
Katherine Luzuriaga
Publication date
01-04-2015
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 3/2015
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-015-0139-3

Other articles of this Issue 3/2015

Journal of Clinical Immunology 3/2015 Go to the issue

Abstracts

2015 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference

CME REVIEW

Human Disease Phenotypes Associated With Mutations in TREX1

Brief Communication

Familial Hepatopulmonary Syndrome in Common Variable Immunodeficiency

Astute Clinician Report

A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele

Original Research

The Duesseldorf Warning Signs for Primary Immunodeficiency: Is it Time to Change the Rules?

Original Research

RAG1 Deficiency May Present Clinically as Selective IgA Deficiency

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits