Interleukin‐37 improves T‐cell‐mediated immunity and chimeric antigen receptor T‐cell therapy in aged backgrounds

Abstract

Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T‐cells and Lat in CD8+ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence.

Current Understanding of IL-37 in Human Health and Disease

“…Therefore, IL-37 functions as an inhibitor of TI and can be a potential therapeutic target in immune-mediated pathologies and host responses against pathogens. human monocytes significantly decreased with age (68). In a recent study, IL-37tg mice mitigates or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of macrophages and DCs in the bone marrow and spleen (68).…”

“…IL-37 restores a youthful gene expression levels of Pdcd1, Lat, and Stat4 in aged CD4+T-cells and Lat in aged CD8+ T-cells, and reduces the surface expression of immunoinhibitory proteins (68). Recombinant IL-37 treatment not only improves T-cell function in aged mice, but also improves the efficacy of aged chimeric antigen receptor T-cells which significantly extended the survival of mice transplanted with leukemia cells (68). Thus, IL-37 can boost the function of aged T-cells and overcome aging-associated immunosenescence.…”

“…In a recent study, IL-37tg mice mitigates or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of macrophages and DCs in the bone marrow and spleen (68). Moreover, IL-37 promotes cytokine production in aged T-cells and reduces the surface expression of programmed cell death protein 1 (68). IL-37 restores a youthful gene expression levels of Pdcd1, Lat, and Stat4 in aged CD4+T-cells and Lat in aged CD8+ T-cells, and reduces the surface expression of immunoinhibitory proteins (68).…”

“…human monocytes significantly decreased with age (68). In a recent study, IL-37tg mice mitigates or prevents aging-associated chronic inflammation, splenomegaly, and accumulation of macrophages and DCs in the bone marrow and spleen (68). Moreover, IL-37 promotes cytokine production in aged T-cells and reduces the surface expression of programmed cell death protein 1 (68).…”

“…Moreover, IL-37 promotes cytokine production in aged T-cells and reduces the surface expression of programmed cell death protein 1 (68). IL-37 restores a youthful gene expression levels of Pdcd1, Lat, and Stat4 in aged CD4+T-cells and Lat in aged CD8+ T-cells, and reduces the surface expression of immunoinhibitory proteins (68). Recombinant IL-37 treatment not only improves T-cell function in aged mice, but also improves the efficacy of aged chimeric antigen receptor T-cells which significantly extended the survival of mice transplanted with leukemia cells (68).…”