Overexpression of FGF21 in thymic stromal cells enhances T cell responses to viral infection and immune checkpoint inhibition efficacy during aging 2259870

Abstract

Abstract Introduction Age-associated thymus atrophy diminishes T cell repertoire diversity, diminishing responsiveness to vaccination, viral infection, and tumor surveillance. Age-associated T cell dysregulation includes the persistence of virus-specific lung tissue resident memory T (Trm) cells in aged mice after influenza infection, driving chronic non-resolving inflammation and lung pathology 60 days post-infection (d.p.i.) Our recent work demonstrated that sustained thymic overexpression of fibroblast growth factor 21 (FGF21) in LPOFGF21 knock-in (KI) mice promotes increased thymic size and naïve T cell export in aged mice, improving age-related declines in CD8+ T cell responses to influenza in the acute phase, at 10 d.p.i. Methods To further test the impact of thymic overexpression of FGF21 on lung Trm and pathology in older mice, we examined immune responses to primary and heterosubtypic secondary challenge in 12—15-month-old LPOWT and LPOFGF21 mice at 7 and 60 d.p.i. Mice were infected intranasally with IAV PR8 only, or with IAV PR8 20 days after primary IAV X31 infection, and were analyzed at 7 or 60 d.p.i. Results Sustained FGF21 overexpression in LPOFGF21 mice mitigated the age-associated accumulation of CD8+ Trm, and the associated chronic lung pathology at 60 d.p.i. It also increased the frequency of T follicular helper and class-switched B cells in mediastinal lymph node at 7 and 60 d.p.i. We also tested the efficacy of immune checkpoint inhibition (ICI, anti-PD-L1 antibody) treatment in young and aged LPOFGF21 KI mice and age-matched controls using a B16 melanoma tumor model. We found that aging impaired tumor control and ICI efficacy in aged control mice, and that these age-associated impairments were ameliorated in age-matched LPOFGF21 KI mice. Conclusion These results suggest that intrathymic FGF21 overexpression mitigates age-associated declines in anti-viral and anti-tumor CD8+ T cell responses, revealing a potential therapeutic target for improving T cell function in aging. Funding Source NIH R01 AG086271 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)