Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection
Tóm tắt
Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses. Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1−/− recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7− TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection. This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.
Tài liệu tham khảo
Shafagati N, Williams J. Human metapneumovirus - what we know now. F1000Res. 2018;7:135.
Falsey AR, Erdman D, Anderson LJ, Walsh EE. Human metapneumovirus infections in young and elderly adults. J Infect Dis. 2003;187(5):785–90.
Hasvold J, Sjoding M, Pohl K, Cooke C, Hyzy RC. The role of human metapneumovirus in the critically ill adult patient. J Crit Care. 2016;31(1):233–7.
van den Hoogen BG, Osterhaus DM, Fouchier RA. Clinical impact and diagnosis of human metapneumovirus infection. Pediatr Infect Dis J. 2004;23(1 Suppl):S25-32.
Widmer K, Zhu Y, Williams JV, Griffin MR, Edwards KM, Talbot HK. Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. J Infect Dis. 2012;206(1):56–62.
Holzemer NF, Hasvold JJ, Pohl KJ, Ashbrook MJ, Meert KL, Quasney MW. Human metapneumovirus infection in hospitalized children. Respir Care. 2020;65(5):650–7.
Eddens T, Parks OB, Williams JV. Neonatal immune responses to respiratory viruses. Front Immunol. 2022;13:863149.
Scheuerman O, Barkai G, Mandelboim M, Mishali H, Chodick G, Levy I. Human metapneumovirus (hMPV) infection in immunocompromised children. J Clin Virol. 2016;83:12–6.
Syha R, Beck R, Hetzel J, Ketelsen D, Grosse U, Springer F, et al. Human metapneumovirus (HMPV) associated pulmonary infections in immunocompromised adults–initial CT findings, disease course and comparison to respiratory-syncytial-virus (RSV) induced pulmonary infections. Eur J Radiol. 2012;81(12):4173–8.
Erickson JJ, Gilchuk P, Hastings AK, Tollefson SJ, Johnson M, Downing MB, et al. Viral acute lower respiratory infections impair CD8+ T cells through PD-1. J Clin Invest. 2012;122(8):2967–82.
Erickson JJ, Rogers MC, Hastings AK, Tollefson SJ, Williams JV. Programmed death-1 impairs secondary effector lung CD8(+) T cells during respiratory virus reinfection. J Immunol. 2014;193(10):5108–17.
Erickson JJ, Lu P, Wen S, Hastings AK, Gilchuk P, Joyce S, et al. Acute viral respiratory infection rapidly induces a CD8+ T cell exhaustion-like phenotype. J Immunol. 2015;195(9):4319–30.
Erickson JJ, Rogers MC, Tollefson SJ, Boyd KL, Williams JV. Multiple Inhibitory pathways contribute to lung CD8+ T cell impairment and protect against immunopathology during acute viral respiratory infection. J Immunol. 2016;197(1):233–43.
Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90.
Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, et al. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz). 2016;64(2):111–26.
Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, et al. Comprehensive profiling of an aging immune system reveals clonal GZMK(+) CD8(+) T cells as conserved hallmark of inflammaging. Immunity. 2021;54(1):99-115 e12.
Angelidis I, Simon LM, Fernandez IE, Strunz M, Mayr CH, Greiffo FR, et al. An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun. 2019;10(1):963.
Li J, He Y, Hao J, Ni L, Dong C. High levels of eomes promote exhaustion of anti-tumor CD8(+) T cells. Front Immunol. 2018;9:2981.
Hu B, Jadhav RR, Gustafson CE, Le Saux S, Ye Z, Li X, et al. Distinct age-related epigenetic signatures in CD4 and CD8 T cells. Front Immunol. 2020;11:585168.
Goplen NP, Wu Y, Son YM, Li C, Wang Z, Cheon IS, et al. Tissue-resident CD8(+) T cells drive age-associated chronic lung sequelae after viral pneumonia. Sci Immunol. 2020;5(53):eabc4557.
Po JL, Gardner EM, Anaraki F, Katsikis PD, Murasko DM. Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev. 2002;123(8):1167–81.
Jiang J, Bennett AJ, Fisher E, Williams-Bey Y, Shen H, Murasko DM. Limited expansion of virus-specific CD8 T cells in the aged environment. Mech Ageing Dev. 2009;130(11–12):713–21.
Verschoor CP, Pawelec G, Haynes L, Loeb M, Andrew MK, Kuchel GA, et al. Granzyme B: a double-edged sword in the response to influenza infection in vaccinated older adults. Front Aging. 2021;2:753767.
McElhaney JE, Ewen C, Zhou X, Kane KP, Xie D, Hager WD, et al. Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine. 2009;27(18):2418–25.
Dolfi DV, Mansfield KD, Polley AM, Doyle SA, Freeman GJ, Pircher H, et al. Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. J Leukoc Biol. 2013;93(6):825–36.
Kolli D, Bataki EL, Spetch L, Guerrero-Plata A, Jewell AM, Piedra PA, et al. T lymphocytes contribute to antiviral immunity and pathogenesis in experimental human metapneumovirus infection. J Virol. 2008;82(17):8560–9.
Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571(7764):211–8.
Lu YJ, Barreira-Silva P, Boyce S, Powers J, Cavallo K, Behar SM. CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection. Cell Rep. 2021;36(11):109696.
Khan SM, Desai R, Coxon A, Livingstone A, Dunn GP, Petti A, et al. Impact of CD4 T cells on intratumoral CD8 T-cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors. J Immunother Cancer. 2022;10(12):e005293.
Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, et al. 4–1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018;215(4):1091–100.
Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976–86.
Darniot M, Pitoiset C, Petrella T, Aho S, Pothier P, Manoha C. Age-associated aggravation of clinical disease after primary metapneumovirus infection of BALB/c mice. J Virol. 2009;83(7):3323–32.
Westmeier J, Paniskaki K, Karakose Z, Werner T, Sutter K, Dolff S, et al. Impaired cytotoxic CD8(+) T cell response in elderly COVID-19 patients. mBio. 2020;11(5):e02243-20.
Mattoo H, Faulkner M, Kandpal U, Das R, Lewis V, George A, et al. Naive CD4 T cells from aged mice show enhanced death upon primary activation. Int Immunol. 2009;21(11):1277–89.
Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M. Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment. Mech Ageing Dev. 2006;127(3):274–81.
Gilchuk P, Spencer CT, Conant SB, Hill T, Gray JJ, Niu X, et al. Discovering naturally processed antigenic determinants that confer protective T cell immunity. J Clin Invest. 2013;123(5):1976–87.
Martinez-Perez AG, Perez-Trujillo JJ, Garza-Morales R, Loera-Arias MJ, Saucedo-Cardenas O, Garcia-Garcia A, et al. 4–1BBL as a mediator of cross-talk between innate, adaptive, and regulatory immunity against cancer. Int J Mol Sci. 2021;22(12):6210.
Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J Exp Med. 2021;218(3):e20192283.
Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27(4):670–84.
Forde PM, Chaft JE, Pardoll DM. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;379(9): e14.
Tserel L, Kolde R, Limbach M, Tretyakov K, Kasela S, Kisand K, et al. Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci Rep. 2015;5:13107.
Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417–21.
Ford BR, Vignali PDA, Rittenhouse NL, Scharping NE, Peralta R, Lontos K, et al. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci Immunol. 2022;7(74):eabj9123.
Williams JV, Tollefson SJ, Johnson JE, Crowe JE Jr. The cotton rat (Sigmodon hispidus) is a permissive small animal model of human metapneumovirus infection, pathogenesis, and protective immunity. J Virol. 2005;79(17):10944–51.
Xu J, Zhang Y, Williams JV. Development and optimization of a direct plaque assay for trypsin-dependent human metapneumovirus strains. J Virol Methods. 2018;259:1–9.
Busch CJ, Favret J, Geirsdottir L, Molawi K, Sieweke MH. Isolation and long-term cultivation of mouse alveolar macrophages. Bio Protoc. 2019;9(14):e3302.
Rock MT, Crowe JE Jr. Identification of a novel human leucocyte antigen-A*01-restricted cytotoxic T-lymphocyte epitope in the respiratory syncytial virus fusion protein. Immunology. 2003;108(4):474–80.