Skip to main content
Top
Published in: Journal of Translational Medicine 1/2014

Open Access 01-12-2014 | Research

High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors

Authors: Diane M Longo, Brent Louie, Jason Ptacek, Greg Friedland, Erik Evensen, Santosh Putta, Michelle Atallah, David Spellmeyer, Ena Wang, Zoltan Pos, Francesco M Marincola, Andrea Schaeffer, Suzanne Lukac, Radha Railkar, Chan R Beals, Alessandra Cesano, Leonidas N Carayannopoulos, Rachael E Hawtin

Published in: Journal of Translational Medicine | Issue 1/2014

Login to get access

Abstract

Background

Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors.

Methods

In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25–40 yrs)].

Results

Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets.

Conclusions

These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies.
Appendix
Available only for authorised users
Literature
1.
go back to reference Boraschi D, Aguado MT, Dutel C, Goronzy J, Louis J, Grubeck-Loebenstein B, Rappuoli R, Del Giudice G: The gracefully aging immune system. Sci Transl Med. 2013, 5: 185ps188-CrossRef Boraschi D, Aguado MT, Dutel C, Goronzy J, Louis J, Grubeck-Loebenstein B, Rappuoli R, Del Giudice G: The gracefully aging immune system. Sci Transl Med. 2013, 5: 185ps188-CrossRef
2.
go back to reference Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB: Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009, 30: 351-359. 10.1016/j.it.2009.05.002.PubMedCentralCrossRefPubMed Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB: Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009, 30: 351-359. 10.1016/j.it.2009.05.002.PubMedCentralCrossRefPubMed
3.
go back to reference Haynes L, Lefebvre JS: Age-related Deficiencies in Antigen-Specific CD4 T cell Responses: Lessons from Mouse Models. Aging Dis. 2011, 2: 374-381.PubMedCentralPubMed Haynes L, Lefebvre JS: Age-related Deficiencies in Antigen-Specific CD4 T cell Responses: Lessons from Mouse Models. Aging Dis. 2011, 2: 374-381.PubMedCentralPubMed
6.
go back to reference Krutzik PO, Irish JM, Nolan GP, Perez OD: Analysis of protein phosphorylation and cellular signaling events by flow cytometry: techniques and clinical applications. Clin Immunol. 2004, 110: 206-221. 10.1016/j.clim.2003.11.009.CrossRefPubMed Krutzik PO, Irish JM, Nolan GP, Perez OD: Analysis of protein phosphorylation and cellular signaling events by flow cytometry: techniques and clinical applications. Clin Immunol. 2004, 110: 206-221. 10.1016/j.clim.2003.11.009.CrossRefPubMed
7.
go back to reference Longo DM, Louie B, Putta S, Evensen E, Ptacek J, Cordeiro J, Wang E, Pos Z, Hawtin RE, Marincola FM, Cesano A: Single-cell network profiling of peripheral blood mononuclear cells from healthy donors reveals age- and race-associated differences in immune signaling pathway activation. J Immunol. 2012, 188: 1717-1725. 10.4049/jimmunol.1102514.PubMedCentralCrossRefPubMed Longo DM, Louie B, Putta S, Evensen E, Ptacek J, Cordeiro J, Wang E, Pos Z, Hawtin RE, Marincola FM, Cesano A: Single-cell network profiling of peripheral blood mononuclear cells from healthy donors reveals age- and race-associated differences in immune signaling pathway activation. J Immunol. 2012, 188: 1717-1725. 10.4049/jimmunol.1102514.PubMedCentralCrossRefPubMed
8.
go back to reference Kornblau SM, Cohen AC, Soper D, Huang YW, Cesano A: Age-related changes of healthy bone marrow cell signaling in response to growth factors provide insight into low risk MDS. Cytometry B Clin Cytom. 2013, doi:10.1002/cyto.b.21125 Kornblau SM, Cohen AC, Soper D, Huang YW, Cesano A: Age-related changes of healthy bone marrow cell signaling in response to growth factors provide insight into low risk MDS. Cytometry B Clin Cytom. 2013, doi:10.1002/cyto.b.21125
9.
go back to reference Purvis N, Stelzer G: Multi-platform, multi-site instrumentation and reagent standardization. Cytometry. 1998, 33: 156-165. 10.1002/(SICI)1097-0320(19981001)33:2<156::AID-CYTO10>3.0.CO;2-T.CrossRefPubMed Purvis N, Stelzer G: Multi-platform, multi-site instrumentation and reagent standardization. Cytometry. 1998, 33: 156-165. 10.1002/(SICI)1097-0320(19981001)33:2<156::AID-CYTO10>3.0.CO;2-T.CrossRefPubMed
10.
go back to reference Wang L, Gaigalas AK, Yan M: Quantitative fluorescence measurements with multicolor flow cytometry. Methods Mol Biol. 2011, 699: 53-65. 10.1007/978-1-61737-950-5_3.CrossRefPubMed Wang L, Gaigalas AK, Yan M: Quantitative fluorescence measurements with multicolor flow cytometry. Methods Mol Biol. 2011, 699: 53-65. 10.1007/978-1-61737-950-5_3.CrossRefPubMed
11.
go back to reference Dmitrienko A, Tamhane AC: Gatekeeping procedures with clinical trial applications. Pharm Stat. 2007, 6: 171-180. 10.1002/pst.291.CrossRefPubMed Dmitrienko A, Tamhane AC: Gatekeeping procedures with clinical trial applications. Pharm Stat. 2007, 6: 171-180. 10.1002/pst.291.CrossRefPubMed
12.
go back to reference Haynes L, Swain SL: Why aging T cells fail: implications for vaccination. Immunity. 2006, 24: 663-666. 10.1016/j.immuni.2006.06.003.CrossRefPubMed Haynes L, Swain SL: Why aging T cells fail: implications for vaccination. Immunity. 2006, 24: 663-666. 10.1016/j.immuni.2006.06.003.CrossRefPubMed
13.
go back to reference Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ: T cell subset-specific susceptibility to aging. Clin Immunol. 2008, 127: 107-118. 10.1016/j.clim.2007.12.002.PubMedCentralCrossRefPubMed Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ: T cell subset-specific susceptibility to aging. Clin Immunol. 2008, 127: 107-118. 10.1016/j.clim.2007.12.002.PubMedCentralCrossRefPubMed
14.
go back to reference Gillis S, Kozak R, Durante M, Weksler ME: Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest. 1981, 67: 937-942. 10.1172/JCI110143.PubMedCentralCrossRefPubMed Gillis S, Kozak R, Durante M, Weksler ME: Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest. 1981, 67: 937-942. 10.1172/JCI110143.PubMedCentralCrossRefPubMed
15.
go back to reference Fehniger TA, Cooper MA, Caligiuri MA: Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 2002, 13: 169-183. 10.1016/S1359-6101(01)00021-1.CrossRefPubMed Fehniger TA, Cooper MA, Caligiuri MA: Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 2002, 13: 169-183. 10.1016/S1359-6101(01)00021-1.CrossRefPubMed
16.
go back to reference Nagel JE, Chopra RK, Powers DC, Adler WH: Effect of age on the human high affinity interleukin 2 receptor of phytohaemagglutinin stimulated peripheral blood lymphocytes. Clin Exp Immunol. 1989, 75: 286-291.PubMedCentralPubMed Nagel JE, Chopra RK, Powers DC, Adler WH: Effect of age on the human high affinity interleukin 2 receptor of phytohaemagglutinin stimulated peripheral blood lymphocytes. Clin Exp Immunol. 1989, 75: 286-291.PubMedCentralPubMed
17.
go back to reference Good KL, Avery DT, Tangye SG: Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J Immunol. 2009, 182: 890-901. 10.4049/jimmunol.182.2.890.CrossRefPubMed Good KL, Avery DT, Tangye SG: Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J Immunol. 2009, 182: 890-901. 10.4049/jimmunol.182.2.890.CrossRefPubMed
18.
go back to reference Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J: CD27(+) (memory) B cell decrease and apoptosis-resistant CD27(-) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. Int Immunol. 2005, 17: 383-390. 10.1093/intimm/dxh218.CrossRefPubMed Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J: CD27(+) (memory) B cell decrease and apoptosis-resistant CD27(-) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. Int Immunol. 2005, 17: 383-390. 10.1093/intimm/dxh218.CrossRefPubMed
19.
go back to reference Longo DM, Louie B, Mathi K, Pos Z, Wang E, Hawtin RE, Marincola FM, Cesano A: Racial differences in B cell receptor signaling pathway activation. J Transl Med. 2012, 10: 113-10.1186/1479-5876-10-113.PubMedCentralCrossRefPubMed Longo DM, Louie B, Mathi K, Pos Z, Wang E, Hawtin RE, Marincola FM, Cesano A: Racial differences in B cell receptor signaling pathway activation. J Transl Med. 2012, 10: 113-10.1186/1479-5876-10-113.PubMedCentralCrossRefPubMed
20.
go back to reference Whisler RL, Chen M, Liu B, Newhouse YG: Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59fyn/p56lck in human T cells. Mech Ageing Dev. 1999, 111: 49-66. 10.1016/S0047-6374(99)00074-3.CrossRefPubMed Whisler RL, Chen M, Liu B, Newhouse YG: Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59fyn/p56lck in human T cells. Mech Ageing Dev. 1999, 111: 49-66. 10.1016/S0047-6374(99)00074-3.CrossRefPubMed
21.
go back to reference Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ: Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012, 18: 1518-1524. 10.1038/nm.2963.PubMedCentralCrossRefPubMed Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ: Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012, 18: 1518-1524. 10.1038/nm.2963.PubMedCentralCrossRefPubMed
22.
go back to reference van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, Medzhitov R, Shaw AC: Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis. 2007, 195: 1590-1597. 10.1086/516788.CrossRefPubMed van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, Medzhitov R, Shaw AC: Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis. 2007, 195: 1590-1597. 10.1086/516788.CrossRefPubMed
23.
go back to reference Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC: Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol. 2010, 184: 2518-2527. 10.4049/jimmunol.0901022.CrossRefPubMed Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC: Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol. 2010, 184: 2518-2527. 10.4049/jimmunol.0901022.CrossRefPubMed
Metadata
Title
High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors
Authors
Diane M Longo
Brent Louie
Jason Ptacek
Greg Friedland
Erik Evensen
Santosh Putta
Michelle Atallah
David Spellmeyer
Ena Wang
Zoltan Pos
Francesco M Marincola
Andrea Schaeffer
Suzanne Lukac
Radha Railkar
Chan R Beals
Alessandra Cesano
Leonidas N Carayannopoulos
Rachael E Hawtin
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2014
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-12-178

Other articles of this Issue 1/2014

Journal of Translational Medicine 1/2014 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

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