Similar articles

Abstract: asthma is a complex and chronic inflammatory airway disease associated with the abnormal activation of immune cells. T-cell senescence is linked to immune dysfunction and persistent inflammation, but the relationship between asthma and T-cell senescence remains unexplored. This study reveals significantly higher percentages of cluster of differentiation 4-positive (CD4⁺) senescent t cells (Tsens) in asthma patients than in healthy controls, while CD8⁺ Tsen percentages do not appear to increase. CD4⁺ Tsen percentages in both the blood and sputum are positively correlated with fractional exhaled nitric oxide (FeNO) values, eosinophil abundance, and T helper type 2 (Th2) cell abundance in the blood. The clinical manifestations of asthma were recreated in a house dust mite (HDM)-induced mouse model. In HDM-exposed mice, CD4⁺ Tsen percentages were also elevated in the lungs. To counteract T-cell senescence, therapeutic interventions, including interleukin-4 (IL-4) antibodies and dexamethasone, were administered to the mice. IL-4 neutralization reduced CD4⁺ Tsen percentages and inhibited p38 mitogen-activated protein kinase (MAPK) activation. Adoptive transfer of CD4⁺ Tsens did not induce spontaneous asthma in phosphate-buffered saline (PBS)-treated mice but exacerbated type 2 inflammation in HDM-treated mice. Our study revealed a significant increase in CD4⁺ Tsen (CD57⁺CD28^-) abundance in asthma patients and suggested that type 2 inflammation drives CD4⁺ T-cell senescence in asthma. Furthermore, adoptive transfer of CD4⁺ Tsens appears to exacerbate type 2 inflammation.

哮喘2型炎症加速CD4⁺ T细胞衰老

[1]AghaliA, KhalfaouiL, LagnadoAB, et al., 2022. Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma. Am J Physiol Lung Cell Mol Physiol, 323(5):L558-L568.

[2]AkbarAN, HensonSM, LannaA, 2016. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol, 37(12):866-876.

[3]BadarA, SalemAM, BamosaAO, et al., 2020. Association between FeNO, total blood IgE, peripheral blood eosinophil and inflammatory cytokines in partly controlled asthma. J Asthma Allergy, 13:533-543.

[4]BauerME, 2020. Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression. Immun Ageing, 17:6.

[5]BussePJ, MathurSK, 2010. Age-related changes in immune function: effect on airway inflammation. J Allergy Clin Immunol, 126(4):690-699.

[6]BussePJ, ZhangTF, SrivastavaK, et al., 2007. Effect of ageing on pulmonary inflammation, airway hyperresponsiveness and T and B cell responses in antigen-sensitized and -challenged mice. Clin Exp Allergy, 37(9):1392-1403.

[7]BussePJ, BirminghamJM, CalatroniA, et al., 2017. Effect of aging on sputum inflammation and asthma control. J Allergy Clin Immunol, 139(6):1808-1818.e6.

[8]ChildsBG, DurikM, BakerDJ, et al., 2015. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med, 21(12):1424-1435.

[9]ChildsBG, GluscevicM, BakerDJ, et al., 2017. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov, 16(10):718-735.

[10]DevulderJV, 2024. Unveiling mechanisms of lung aging in COPD: a promising target for therapeutics development. Chin Med J Pulm Crit Care Med, 2(3):133-141.

[11]Escamilla-GilJM, Fernandez-NietoM, AcevedoN, 2022. Understanding the cellular sources of the fractional exhaled nitric oxide (FeNO) and its role as a biomarker of type 2 inflammation in asthma. Biomed Res Int, 2022:5753524.

[12]GasekNS, KuchelGA, KirklandJL, et al., 2021. Strategies for targeting senescent cells in human disease. Nat Aging, 1(10):870-879.

[13]GBD Chronic Respiratory Disease Collaborators, 2020. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med, 8(6):585-596.

[14]GorgoulisV, AdamsPD, AlimontiA, et al., 2019. Cellular senescence: defining a path forward. Cell, 179(4):813-827.

[15]HammadH, LambrechtBN, 2021. The basic immunology of asthma. Cell, 184(9):2521-2522.

[16]HuangKW, YangT, XuJY, et al., 2019. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study. Lancet, 394(10196):407-418.

[17]JudgeSJ, MurphyWJ, CanterRJ, 2020. Characterizing the dysfunctional NK cell: assessing the clinical relevance of exhaustion, anergy, and senescence. Front Cell Infect Microbiol, 10:49.

[18]KimHD, YuSJ, KimHS, et al., 2013. Interleukin-4 induces senescence in human renal carcinoma cell lines through STAT6 and p38 MAPK. J Biol Chem, 288(40):28743-28754.

[19]LambersC, HackerS, PoschM, et al., 2009. T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin Exp Immunol, 155(3):466-475.

[20]López-OtínC, BlascoMA, PartridgeL, et al., 2023. Hallmarks of aging: an expanding universe. Cell, 186(2):243-278.

[21]MadrugaMP, GrunLK, Dos SantosLSM, et al., 2024. Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients. Immun Ageing, 21:17.

[22]MendelsohnAR, LarrickJW, 2022. Antiaging vaccines targeting senescent cells. Rejuvenation Res, 25(1):39-45.

[23]MinSN, ZhuMQ, MaoXD, et al., 2022. Contribution of interleukin-4-induced epithelial cell senescence to glandular fibrosis in IgG4-related sialadenitis. Arthritis Rheumatol, 74(6):1070-1082.

[24]MittelbrunnM, KroemerG, 2021. Hallmarks of T cell aging. Nat Immunol, 22(6):687-698.

[25]ÖdlingM, AnderssonN, EkströmS, et al., 2018. Characterization of asthma in the adolescent population. Allergy, 73(8):1744-1746.

[26]PelletierG, GodboutK, BoulayMÈ, et al., 2022. Increase in FeNO levels following IL5/IL5R-targeting therapies in severe asthma: a case series. J Asthma Allergy, 15:691-701.

[27]SchaferMJ, WhiteTA, IijimaK, et al., 2017. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun, 8:14532.

[28]ShirakawaK, YanXX, ShinmuraK, et al., 2016. Obesity accelerates T cell senescence in murine visceral adipose tissue. J Clin Invest, 126(12):4626-4639.

[29]SomaT, NagataM, 2022. Immunosenescence, inflammaging, and lung senescence in asthma in the elderly. Biomolecules, 12(10):1456.

[30]SturmlechnerI, ZhangC, SineCC, et al., 2021. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science, 374(6567):eabb3420.

[31]WanRJ, SrikaramP, GuntupalliV, et al., 2023. Cellular senescence in asthma: from pathogenesis to therapeutic challenges. eBioMedicine, 94:104717.

[32]WangK, StonhamC, RutherfordC, et al., 2023. Fractional exhaled nitric oxide (FeNO): the future of asthma care? Br J Gen Pract, 73(737):565-568.

[33]WangTW, JohmuraY, SuzukiN, et al., 2022. Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature, 611(7935):358-364.

[34]WangZN, SuRN, YangBY, et al., 2020. Potential role of cellular senescence in asthma. Front Cell Dev Biol, 8:59.

[35]WeyandCM, YangZ, GoronzyJJ, 2014. T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol, 26(1):93-100.

[36]WoodWA, KrishnamurthyJ, MitinN, et al., 2016. Chemotherapy and stem cell transplantation increase p16^INK4a expression, a biomarker of T-cell aging. eBioMedicine, 11:227-238.

[37]YangJ, LiuHC, ZhangJQ, et al., 2023. The effect of metformin on senescence of T lymphocytes. Immun Ageing, 20:73.

[38]YoshidaS, NakagamiH, HayashiH, et al., 2020. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat Commun, 11:2482.

[39]YudaE, AndoT, IshidaY, et al., 2025. Investigation of individual variability and temporal fluctuations in exhaled nitric oxide (FeNO) levels in healthy individuals. Adv Respir Med, 93(4):26.

[40]ZhangJ, ChangC, LiangZY, et al., 2025. Elevated CD4⁺ T cell senescence associates with impaired immune responsiveness in severe COVID-19. Aging Dis, 16(1):498-511.

[41]ZhangPZ, CattersonJH, GrönkeS, et al., 2024. Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system. Nat Aging, 4(4):491-509.