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

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Immunity & Ageing
Published in: Immunity & Ageing 1/2018

Open Access 01-12-2018 | Research

Molecular changes associated with increased TNF-α-induced apoptotis in naïve (TN) and central memory (TCM) CD8+ T cells in aged humans

Authors: Sudhir Gupta, Houfen Su, Sudhanshu Agrawal, Sastry Gollapudi

Published in: Immunity & Ageing | Issue 1/2018

Login to get access

Abstract

Background

Progressive T cell decline in aged humans is associated with a deficiency of naïve (TN) and central memory (TCM) T cells. We have previously reported increased Tumor necrosis factor-α (TNF-α)-induced apoptosis in TN and TCM T cells in aged humans; however, the molecular basis of increased apoptosis remains to be defined. Since expression of TNF receptors (TNFRs) was reported to be comparable in young and aged, we investigated signaling events downstream of TNFRs to understand the molecular basis of increased TNF-α-induced apoptosis in aged TN and TCM CD8+ cells.

Results

The expression of TRAF-2 and RIP, phosphorylation of JNK, IKKα/β, and IκBα, and activation of NF-κB activation were significantly decreased in TN and TCM CD8+ cells from aged subjects as compared to young controls. Furthermore, expression of A20, Bcl-xL, cIAP1, and FLIP-L and FLIP-S was significantly decreased in TN and TCM CD8+ cells from aged subjects.

Conclusions

These data demonstrate that an impaired expression/function of molecules downstream TNFR signaling pathway that confer survival signals contribute to increased apoptosis of TN and TCM CD8+ cells in aged humans.
Literature
1.
2.
Vallejo AN. Immune aging and challenges for immune protection of the graying population. Aging Disease. 2011;2:339–45.PubMedPubMedCentral
3.
Sansoni P, Vescivini R, Biasini C, Zanni F, Telera A, Lucchini G, Passeri G, Monti G, Frnchesi C, Passeri M. The Imune system in extreme longevity. Exp Gerontol. 2008;43:61–5.CrossRefPubMed
4.
Pawlec G, Larbi A, Derhovanessian E. Senescence of the human immune system. J Compl Pathol. 2010;42(suppl 1):S39–44.CrossRef
5.
Pawelec G, Hirokawa K, Fulop T. Altered T cell signaling in ageing. Mech Ageing Dev. 2001;122:1613–37.CrossRefPubMed
6.
Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatric Soc. 1993;41:176–81.CrossRef
7.
Gupta S. Membrane signal transduction in T cells in aging humans. Annals of NY Acad Sciences. 1989;568:277–82.CrossRef
8.
Powlec G, Barnett Y, Effros R, Forsey R, Frasca D, Globerson A, Mariani E, McLeod J, Caruso C, Franceschi C, Fulop T, Gupta S, Mocchegiani E, Solana R. T cells and aging. Front Biosci. 2002;7:d1058–183.
9.
Fagiola U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol. 1993;23:2375–8.CrossRef
10.
Brunnsgaard H, Andersen-Ranberg K, Hjelmborg JB, Pedersen BK, Jeu B. Elevated tumor necrosis factor alpha and mortality in centenarians. Amer J Med. 2003;115:278–83.CrossRef
11.
Trzonkowski P, Myslizska J, Godlewska B, Szmit E, Lukaszuk K, Wieckiewicz J, Brydak L, Machala M, Landowski J, Mysliwski A. Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients. Brain Behav Immun. 2004;18:135–48.CrossRefPubMed
12.
Penninx BWJH, Kritchevsky SB, Newman AB, Nicklas BJ, Simonsick EM, Rubin S, Nevitt M, Visser M, Harris T, Pahor M. Inflammatory markers and incident mortality limitation in the elderly. J Amer Gerontol Soc. 2004;52:1105–13.
13.
Kaech SM, Ahmed R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nature Immunol. 2001;2:415–22.
14.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–12.CrossRefPubMed
15.
Masopust D, Vezys V, Marzo AL, Lanzavecchia A. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291:2413–7.CrossRefPubMed
16.
Weninger W, Crowley MA, Manjunath N, von Andriane UH. Migratory properties of naïve, effector, and memory CD8(+) T cells. J Exp Med. 2001;194:953–66.CrossRefPubMedPubMedCentral
17.
Tomiyama H, Matsuda T, Takiguchi M. Differentiation of CD8+ T cells from a memory to memory/effector phenotype. J Immunol. 2002;168:5538–50.CrossRefPubMed
18.
Geginat J, Lanzvecchia A, Sallusto F. Proliferation and differentiation of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood. 2003;101:4260–6.CrossRefPubMed
19.
Van Lier RAW, ten Berge IJM, Gamadia LE. Human CD8+ T cell differentiation in response to viruses. Nat Rev Immunol. 2003;3:931–8.CrossRefPubMed
20.
Gupta S, Bi R, Su K, Yel L, Chiplunkar S, Gollapudi S. Characterization of naïve/memory effector subsets of CD8+ T cells: changes in aged humans. Exp Gerontology. 2004;20:545–50.CrossRef
21.
Gupta S, Gollapudi S. Molecular mechanisms of TNF-α-induced apoptosis in naïve and memory T cell subsets. Autoimmun Rev. 2006;5:264–8.CrossRefPubMed
22.
Gupta S. Molecular mechanisms of TNF-α-induced apoptosis in naïve and memory T cell subsets: effect of age. Immunol Rev. 2005;205:114–25.CrossRefPubMed
23.
Gupta S, Bi R, Gollapudi S. Differential sensitivity of naïve and central and effector memory CD8+ T cells to TNF-α-induced apoptosis. J Clin Immunol. 2006;26:193–203.CrossRefPubMed
24.
Gupta S, Gollapudi S. Central and effector memory CD4+ and CD8+ T cells display differential sensitivity to TNF-α-induced apoptosis. N Y Acad Sci. 2005;1050:108–14.CrossRef
25.
Salvioli S, Capri M, Scarcella E, Mangherini S, Faranca I, Volterra V, De Ronchi D, Marini M, Bonafe M, Franceschi C, Monti D. Age-dependent changes in the susceptibility to apoptosis of peripheral blood CD4+ and CD8+ T lymphocytes with virgin or memory phenotype. Mech Ageing Dev. 2003;124:409–18.CrossRefPubMed
26.
27.
Screaton G, Xu X-N. T cell life and death signaling via TNF-receptor family members. Curr Opin Immunol. 2000;12:316–3222.CrossRefPubMed
28.
Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45–65.CrossRefPubMed
29.
Gupta S. Molecular steps of TNF receptor-mediated apoptosis. Curr Mol Med. 2001;1:299–306.CrossRef
30.
31.
Vallabhapurapu S, Karin M. Regulation and function of NFkappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733.CrossRefPubMed
32.
33.
Li Q, Verma IM. NF-κB regulation in the immune system. Nature Rev Immunol. 2002;2:725–34.CrossRef
34.
35.
36.
Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Z-g L. The distinct role of TRAF2 and RIP in IKK activation by TNFR1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity. 2000;12:419–29.CrossRefPubMed
37.
Michaeu O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.CrossRef
38.
Deng Y, Ren X, Yang L, Lin Y, Wu X. A JNK-dependent pathway is required for TNF-α-induced apoptosis. Cell. 2003;115:61–70.CrossRefPubMed
39.
Aggarwal S, Gollapudi S, Gupta S. Increased TNF-α-induced apoptosis in lymphocytes from aged humans: changes in TNF-α receptor expression and activation of caspases. J Immunol. 1999;162:2154–61.PubMed
40.
Aggarwal S, Gupta S. Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Bcl-2 and Bax. J Immunol. 1998;160:1627–37.PubMed
41.
Gupta S, Gollapudi S. Susceptibility of naïve and subsets of memory T cells to apoptosis via multiple signaling pathways. Autoimmunity Rev. 2007;6:476–81.CrossRef
42.
Gupta S, Gollapudi S. CD95-mediated apoptosis in naïve, central, and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol. 2008;43:266–74.CrossRefPubMed
43.
Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Francechi C, Passeri M, Sansoni P. Shortage of circulating naïve CD8+ T cells provides new insights on immunodeficiency in aging. Blood. 2000;95:2860–8.PubMed
44.
Romanyukha AA, Yashin AI. Age-related changes in population of peripheral T cells: towards a model of immunosenescence. Mech Ageing Dev. 2003;124:433–43.CrossRefPubMed
45.
Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause of both in vivo and in vitro immunosenescence. Exp Gerontol. 1994;29:601–9.CrossRefPubMed
46.
Nociari MM, Telford W, Russo C. Postthymic development of CD28-CD8+ T cell subsets: age-associated expansion and shift from naïve to memory phenotype. J Immunol. 1999;162:3327–35.PubMed
47.
Brzezinska A, Magalska A, Szybinska A, Sikora E. Proliferation and apoptosis of human CD8+CD28+ and CD8+CD28- lymphocytes during aging. Exp Gerontol. 2004;39:539–44.CrossRefPubMed
48.
Gupta S, Gollapudi S. TNF-α-induced apoptosis in human naïve and memory CD8+ T cells in aged humans. Exp Gerontol. 2006;41:69–77.CrossRefPubMed
49.
Broglie P, Matsumoto K, Akira S, Brautigan DL, Ninomiya-Tsuji J. Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway. J Biol Chem. 2010;285:2333–9.CrossRefPubMed
50.
Adhikari A, Xu M, Chen ZJ. Ubiquitin-mediated activation of TAK-1 and IKK. Oncogene. 2007;26:3214–26.CrossRefPubMed
51.
Huang C-H, Omori E, Akira S, Matsumoto K, Ninomiya-Tsuji J. Osmotic stress activates the TAK1-JNK opathway while blocking TAK1-mediated NF-κB activation: TAO2 regulates TAK1. J Biol Chem. 2006;281:28802–10.CrossRef
52.
53.
Irmler M, Thome M, Hahne M, Schnieder P, Hoffmann K, Steiner V, Bodmer J-L, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–5.CrossRefPubMed
54.
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J. The caspases-8 inhibitor FLIP promotes activation of NF-kappaB and ERK signaling pathways. Curr Biol. 2000;10:640–8.CrossRefPubMed
55.
Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nature Rev Mol Cell Biol. 2004;3:401–10.CrossRef
56.
Heyninck K, Beyaert R. A20 inhibits NF-κB activation by dual ubiquitin-editing functions. Trends Biochem Sci. 2005;30:1–4.CrossRefPubMed
57.
Lin S-C, Chung JY, Lamothe B, Rajashanker K, Lu M, Lo Y-C, Lam AY, Darnay BG, Wu H. Molecular basis for the deubiquitinating activity of the NF-κB inhibitor A20. J Mol Biol. 2008;376:526–40.CrossRefPubMed
58.
Komander D, Barford DS. Structure of the A20 OUT domain and mechanistic insight into deubiquitination. Biochem J. 2008;408:77–85.CrossRef
59.
Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T, Tohyama M. Tumor necrosis factor-induces Bcl-2 and Bcl-x expression through NF-κB activation in primary hippocampus neurons. J Biol Chem. 1999;274:8531–8.CrossRefPubMed
60.
Chen C, Edelstein LC, Gelinas C. The Rel/NF-κB family directly activates expression of the apoptotic inhibitor Bcl-x (L). Mol Cell Biol. 2000;20:2687–95.CrossRefPubMedPubMedCentral
61.
Gupta S, Kim H, Yel L, Gollapudi S. A role of fas-associated death domain (FADD) in increased apoptosis in aged humans. J Clin Immunol. 2004;24:24–9.CrossRefPubMed
62.
63.
Xia Z-P, Chen ZJ. TRAF2: a double edge sword? Science Stke. 2005;72:1–4.
64.
Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002;115:679–88.PubMed
65.
Sun L, Chen J. The novel functions of ubiquiination in signaling. Curr Opin Cell Biol. 2004;16:119–26.CrossRefPubMed
66.
67.
Wu C-J, Conze DB, Li T, Srinivasula SM, Ashwell JD. Sensing of Lys63-linked polyubiquitination by NEMO is a key event in NF-κB activation. Nature Cell Biol. 2006;8:398–406.CrossRefPubMed
68.
Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell. 2006;22:245–57.CrossRefPubMed
69.
Li H, Kobayashi M, Blonska M, You Y, Lin X. Ubiquitination of RIP is required for tumor necrosis factor-α-induced NF-κB activation. J Biol Chem. 2006;281:13636–43.CrossRefPubMed
70.
Israel A. NF-kB activation. Nondegenerative ubiquitination implicates NEMO. Trends Immunol. 2006;27:395–7.CrossRefPubMed
71.
Morioka S, Broglie P, Omori E, Ikeda Y, Takaesu G, Matsumoto K, Ninomiya-Tsuji J. TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol. 2014;204:607–23.CrossRefPubMedPubMedCentral
72.
Shim J-H, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee K-Y, Bussey C, Steckel M, Tanaka N, Yamada AS, Matsumoto K, Ghosh S. TAK1, but not TAB1 or TAB2, plays an G essential role in multiple signaling pathways in vivo. Genes Dev. 2005;19:2668–81.CrossRefPubMedPubMedCentral
73.
Pujari R, Hunte R, Khan WN, Shembade N. A20-mediated negative regulation of canonical NF-kB signaling pathway. Immunol Res. 2013;57:166–71.CrossRefPubMed
74.
75.
Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, Enwere E, Arora V, Mak TW, Lacasse EC, Waring J, Korneluk RG. Both cIAP1 and cIAP2 regulate TNF-α-mediated NF-κB activation. Proc Nat Acad Sci (USA). 2008;105:11778–83.CrossRef
76.
Gupta S. A role of inhibitor of apoptosis (IAP) proteins in increased TNF-α-induced apoptosis in lymphocytes from aged humans. Mech Ageing Dev. 2004;125:99–101.CrossRefPubMed
77.
78.
Kataoka T, Tschopp J. N-termina fragment of cFLIP (L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-κB activation. Mol Cell Biol. 2004;24:2627–36.CrossRefPubMedPubMedCentral
79.
Matsuda I, Matsuo K, Matsushita Y, Haruna Y, Niwa M, Kataoka T. The C-terminal domain of the long form of cellular FLICE-inhibitory protein (c-FLIPL) inhibits the interaction of the caspase 8 prodomain with the receptor-interacting protein 1 (RIP1) death domain and regulates caspase 8-dependent nuclear factor κB (NF-κB) activation. J Biol Chem. 2014;289:3876–87.CrossRefPubMedPubMedCentral
Metadata
Title
Molecular changes associated with increased TNF-α-induced apoptotis in naïve (TN) and central memory (TCM) CD8+ T cells in aged humans
Authors
Sudhir Gupta
Houfen Su
Sudhanshu Agrawal
Sastry Gollapudi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Immunity & Ageing / Issue 1/2018
Electronic ISSN: 1742-4933
DOI
https://doi.org/10.1186/s12979-017-0109-0

Other articles of this Issue 1/2018

Immunity & Ageing 1/2018 Go to the issue

Research

Aged mice display altered numbers and phenotype of basophils, and bone marrow-derived basophil activation, with a limited role for aging-associated microbiota

Research

Different age-independent effects of nutraceutical combinations on endothelium-mediated coronary flow reserve

Research

Expression changes of autophagy-related proteins in AKI patients treated with CRRT and their effects on prognosis of adult and elderly patients

Research

Virtual memory cells make a major contribution to the response of aged influenza-naïve mice to influenza virus infection

Research

CD56bright cells respond to stimulation until very advanced age revealing increased expression of cellular protective proteins SIRT1, HSP70 and SOD2

Correction

Correction to: Virtual memory cells make a major contribution to the response of aged influenza-naïve mice to influenza virus infection

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear 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