Open AccessGlobal analyses revealed age‐related alterations in innate immune responses after stimulation of pathogen recognition receptors
Author(s) -
Metcalf Talibah U.,
Cubas Rafael A.,
Ghneim Khader,
Cartwright Michael J.,
Grevenynghe Julien Van,
Richner Justin M.,
Olagnier David P.,
Wilkinson Peter A.,
Cameron Mark J.,
Park Byung S.,
Hiscott John B.,
Diamond Michael S.,
Wertheimer Anne M.,
NikolichZugich Janko,
Haddad Elias K.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12320
Subject(s) - biology , immunology , innate immune system , acquired immune system , chemokine , immune system , population , monocyte , t cell , cytokine , peripheral blood mononuclear cell , tlr7 , toll like receptor , medicine , biochemistry , environmental health , in vitro
Summary Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells ( PBMC s), we first undertook transcriptional profiling and found that PBMC s isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR 4, TLR 7/8, and RIG ‐I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro‐inflammatory and antiviral cytokines and chemokines including TNF α, IL ‐6, IL ‐1β, IFN α, IFN γ, CCL 2, and CCL 7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMC s from old subjects also had a lower frequency of CD 40+ monocytes, impaired up‐regulation of PD ‐L1 on monocytes and T cells, and increased expression of PD ‐L2 and B7‐H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR ‐stimulated PBMC s (minus CD 3 T cells) from old subjects elicited significantly lower levels of adult T‐cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction ( MLR ). Collectively, these age‐associated changes in cytokine, chemokine and interferon production, as well as co‐stimulatory protein expression could contribute to the blunted memory B‐ and T‐cell immune responses to vaccines and infections.