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

Journal of Translational Medicine

Rachael E Hawtin¹  Leonidas N Carayannopoulos⁴  Alessandra Cesano¹  Chan R Beals⁴  Radha Railkar⁴  Suzanne Lukac⁴  Andrea Schaeffer⁴  Francesco M Marincola²  Zoltan Pos³  Ena Wang²  David Spellmeyer¹  Michelle Atallah¹  Santosh Putta¹  Erik Evensen¹  Greg Friedland¹  Jason Ptacek¹  Brent Louie¹  Diane M Longo¹ 

[1] Nodality, South San Francisco, CA 94080, USA;Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, and Center for Human Immunology, National Institutes of Health, Bethesda, MD 20892, USA;MTA-SE “Lendület” Experimental and Translational Immunomics Research Group, Budapest H-1089, Hungary;Merck & Co., Inc, Rahway, NJ 07065, USA

关键词: Immune signaling;    Aging;    Systems immunology;    Multi-parameter flow cytometry;   

Others  :  803724
DOI  :  10.1186/1479-5876-12-178

 received in 2014-02-11, accepted in 2014-06-16,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Longo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]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.
• [2]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.
• [3]Haynes L, Lefebvre JS: Age-related Deficiencies in Antigen-Specific CD4 T cell Responses: Lessons from Mouse Models. Aging Dis 2011, 2:374-381.
• [4]Goronzy JJ, Weyand CM: Understanding immunosenescence to improve responses to vaccines. Nat Immunol 2013, 14:428-436.
• [5]Goronzy JJ, Li G, Yang Z, Weyand CM: The janus head of T cell aging - autoimmunity and immunodeficiency. Front Immunol 2013, 4:131.
• [6]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.
• [7]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.
• [8]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]Purvis N, Stelzer G: Multi-platform, multi-site instrumentation and reagent standardization. Cytometry 1998, 33:156-165.
• [10]Wang L, Gaigalas AK, Yan M: Quantitative fluorescence measurements with multicolor flow cytometry. Methods Mol Biol 2011, 699:53-65.
• [11]Dmitrienko A, Tamhane AC: Gatekeeping procedures with clinical trial applications. Pharm Stat 2007, 6:171-180.
• [12]Haynes L, Swain SL: Why aging T cells fail: implications for vaccination. Immunity 2006, 24:663-666.
• [13]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.
• [14]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.
• [15]Fehniger TA, Cooper MA, Caligiuri MA: Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev 2002, 13:169-183.
• [16]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.
• [17]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.
• [18]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.
• [19]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. BioMed Central Full Text
• [20]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.
• [21]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.
• [22]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.
• [23]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.