Abstract
In both mice and humans, the CD8 T cell compartment is expanded with age in the presence of a cytomegalovirus (CMV) infection due to an absolute increase in the CD8+ T cell effector memory (TEM) cells. It has been hypothesized that in CMV+ subjects, such accumulated TEM cells could interfere with responses to new infection by competing for space/resources or could inhibit new responses by other, undefined, means. Here we present evidence against this hypothesis. We show that MCMV-specific CD8 T cells accumulate in blood and bone marrow, but not lymph nodes (frequent sites of immune response initiation), in either persistent lifelong CMV infection or following reactivation. Moreover, adoptive transfer of effector memory T cells from MCMV positive mice into naïve animals did not interfere with either humoral or cellular response to West Nile virus or Listeria monocytogenes infection in recipient mice. We conclude that MCMV infection is unlikely to inhibit new immune responses in old animals through direct interference of MCMV-specific CD8 T cells with the priming.
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Abbreviations
- CMV:
-
Cytomegalovirus
- LN:
-
Lymph nodes
- MCMV:
-
Murine CMV
- TEM :
-
T effector memory cells
- WNV:
-
West Nile virus
References
Aiello AE, Chiu YL, Frasca D (2017) How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? GeroScience 39(3):261–271. https://doi.org/10.1007/s11357-017-9983-9
Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Žugich J (2009) Key role of T cell defects in age-related vulnerability to West Nile virus. J Exp Med 206(12):2735–2745. https://doi.org/10.1084/jem.20090222
Bronze MS, Drevets DA (2008) Listeria monocytogenes: epidemiology, human disease, and mechanisms of brain invasion. FEMS Immunol Med Microbiol 53(2):151–165. https://doi.org/10.1111/j.1574-695X.2008.00404.x
Busch DH, Fräßle SP, Sommermeyer D, Buchholz VR, Riddell SR (2016) Role of memory T cell subsets for adoptive immunotherapy. Semin Immunol 28(1):28–34. https://doi.org/10.1016/J.SMIM.2016.02.001
Cicin-Sain L, Brien JD, Uhrlaub JL, Drabig A, Marandu TF, Nikolich-Žugich J (2012) Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog 8(8):e1002849. https://doi.org/10.1371/journal.ppat.1002849
Condotta SA, Richer MJ, Badovinac VP, Harty JT (2012) Probing CD8 T cell responses with Listeria monocytogenes infection. Adv Immunol 113:51–80. https://doi.org/10.1016/B978-0-12-394590-7.00005-1
Conlan JW (1996) Early pathogenesis of Listeria monocytogenes infection in the mouse spleen. J Med Microbiol 44(1996):295–302
Cook CH, Trgovcich J, Zimmerman PD, Zhang Y, Sedmak DD (2006) Lipopolysaccharide, tumor necrosis factor alpha, or interleukin-1 triggers reactivation of latent cytomegalovirus in immunocompetent mice. J Virol 80(18):9151–9158. https://doi.org/10.1128/JVI.00216-06
Geerman S, Hickson S, Brasser G, Pascutti MF, Nolte MA (2016) Quantitative and qualitative analysis of bone marrow CD8+ T cells from different bones uncovers a major contribution of the bone marrow in the vertebrae. Front Immunol 6(JAN):1–11. https://doi.org/10.3389/fimmu.2015.00660
Goerig NL, Frey B, Korn K, Fleckenstein B, Überla K, Schmidt MA, Dörfler A, Engelhorn T, Eyüpoglu I, Rühle PF, Putz F, Semrau S, Gaipl US, Fietkau R (2016) Frequent occurrence of therapeutically reversible CMV-associated encephalopathy during radiotherapy of the brain. Neuro-Oncology 18(12):1664–1672. https://doi.org/10.1093/neuonc/now120
Jackson SE, Redeker A, Arens R, van Baarle D, van den Berg SPH, Benedict CA, Čičin-Šain L, Hill AB, Wills MR (2017) CMV immune evasion and manipulation of the immune system with aging. GeroScience 39(3):273–291. https://doi.org/10.1007/s11357-017-9986-6
Jergović M, Smithey MJ, Nikolich-Žugich J (2018) Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging. Exp Gerontol 105:140–145. https://doi.org/10.1016/j.exger.2018.01.011
Karrer U, Sierro S, Wagner M, Oxenius A, Hengel H, Koszinowski UH, Phillips RE, Klenerman P (2003) Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 170(4):2022–2029. https://doi.org/10.4049/jimmunol.170.4.2022
Leng SX, Kamil J, Purdy JG, Lemmermann NA, Reddehase MJ, Goodrum FD (2017) Recent advances in CMV tropism, latency, and diagnosis during aging. GeroScience 39(3):251–259. https://doi.org/10.1007/s11357-017-9985-7
Marandu TF, Oduro JD, Borkner L, Dekhtiarenko I, Uhrlaub JL, Drabig A, Kröger A, Nikolich-Žugich J, Cicin-Sain L (2015) Immune protection against virus challenge in aging mice is not affected by latent herpesviral infections. J Virol 89(22):11715–11717. https://doi.org/10.1128/JVI.01989-15
Mekker A, Tchang VS, Haeberli L, Oxenius A, Trkola A, Karrer U (2012) Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog 8(8):e1002850. https://doi.org/10.1371/journal.ppat.1002850
Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB (2006) Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 177(1):450–458. https://doi.org/10.4049/jimmunol.177.1.450
Nikolich-Žugich J, Goodrum F, Knox K, Smithey MJ (2017) Known unknowns: how might the persistent herpesvirome shape immunity and aging? Curr Opin Immunol 48:23–30. https://doi.org/10.1016/J.COI.2017.07.011
Pawelec G, Akbar A, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A (2004) Is immunosenescence infectious? Trends Immunol 25(8):406–410. https://doi.org/10.1016/j.it.2004.05.006
Polic B, Hengel H, Krmpotic A, Trgovcich J, Pavic I, Luccaronin P et al (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188(6):1047–1054. https://doi.org/10.1084/jem.188.6.1047
Prösch S, Wendt CEC, Reinke P, Priemer C, Oppert M, Krüger DH, Volk HD, Döcke WD (2000) A novel link between stress and human cytomegalovirus (HCMV) infection: sympathetic hyperactivity stimulates HCMV activation. Virology 272(2):357–365. https://doi.org/10.1006/viro.2000.0367
Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee J, Olshen RA (2014) Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci 111:13139 LP-13144:13139–13144. https://doi.org/10.1073/pnas.1409155111
Smithey MJ, Renkema KR, Rudd BD, Nikolich-Žugich J (2011) Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur J Immunol 41(5):1352–1364. https://doi.org/10.1002/eji.201041141
Smithey MJ, Li G, Venturi V, Davenport MP, Nikolich-Žugich J (2012) Lifelong persistent viral infection alters the naive T cell Pool, impairing CD8 T cell immunity in late life. J Immunol 189(11):5356–5366. https://doi.org/10.4049/jimmunol.1201867
Smithey MJ, Venturi V, Davenport MP, Buntzman AS, Vincent BG, Frelinger JA, Nikolich-Žugich J (2018) Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection. Proc Natl Acad Sci 115(29):E6817–E6825. https://doi.org/10.1073/pnas.1719451115
Souquette A, Frere J, Smithey M, Sauce D, Thomas PG (2017) A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. GeroScience 39(3):293–303. https://doi.org/10.1007/s11357-017-9982-x
Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, Sleath PR, Grabstein KH, Hosken NA, Kern F, Nelson JA, Picker LJ (2005) Broadly targeted human cytomegalovirus-specific CD4 + and CD8 + T cells dominate the memory compartments of exposed subjects. J Exp Med 202(5):673–685. https://doi.org/10.1084/jem.20050882
Torti N, Oxenius A (2012) T cell memory in the context of persistent herpes viral infections. Viruses 4(7):1116–1143. https://doi.org/10.3390/v4071116
Uhrlaub JL, Brien JD, Widman DG, Mason PW, Nikolich-Žugich J (2011) Repeated in vivo stimulation of T and B cell responses in old mice generates protective immunity against lethal West Nile virus encephalitis. J Immunol 186(7):3882–3891. https://doi.org/10.4049/jimmunol.1002799
Yim R, Posfay-barbe KM, Nolt D, Fatula G, Wald ER (2005) Spectrum of clinical manifestations of West Nile virus. Emerg Infect Dis 11(8):1673–1675. https://doi.org/10.1542/peds.2004-0491
Funding
This study is supported by the USPS award AG048021 from the NIH/NIA to JNZ.
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Jergović, M., Uhrlaub, J.L., Contreras, N.A. et al. Do cytomegalovirus-specific memory T cells interfere with new immune responses in lymphoid tissues?. GeroScience 41, 155–163 (2019). https://doi.org/10.1007/s11357-019-00068-0
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DOI: https://doi.org/10.1007/s11357-019-00068-0