IFNγ Transcribed by IRF1 in CD4⁺ Effector Memory T Cells Promotes Senescence-Associated Pulmonary Fibrosis

Abstract

Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells affecting alveolar type II epithelial (AT2) cells, which promote the pathogenesis of senescence-associated pulmonary fibrosis (SAPF). Cell proportions, the relationship between SAPD and T cells, and the aging-and senescence-associated secretory phenotype (SASP) of T cells between young and aged mice were analyzed using lung single-cell transcriptomics. SAPD was monitored by markers of AT2 cells and found to be induced by T cells. Furthermore, IFNγ signaling pathways were activated and cell senescence, SASP, and T cell activation were shown in aged lungs. Physiological aging led to pulmonary dysfunction and TGF-β1/IL-11/MEK/ERK (TIME) signaling-mediated SAPF, which was induced by senescence and SASP of aged T cells. Especially, IFNγ was produced by the accumulated CD4 + effector memory T (TEM) cells in the aged lung. This study also found that physiological aging increased pulmonary CD4 + TEM cells, IFNγ was produced mainly by CD4 + TEM cells, and pulmonary cells had increased responsiveness to IFNγ signaling. Specific regulon activity was increased in T cell subclusters. IFNγ transcriptionally regulated by IRF1 in CD4 + TEM cells promoted the epithelial-to-mesenchymal transition by activating TIME signaling and cell senescence of AT2 cells with aging. Accumulated IRF1 + CD4 + TEM produced IFNγ in lung with aging and anti-IRF1 primary antibody treatment inhibited the expression of IFNγ. Aging might drive T cell differentiation toward helper T cells with developmental trajectories and enhance cell interactions of pulmonary T cells with other surrounding cells. Thus, IFNγ transcribed by IRF1 in CD4 + effector memory T cells promotes SAPF. IFNγ produced by CD4 + TEM cells in physiologically aged lungs could be a therapeutic target for preventing SAPF.

Persistence of lung structural and functional alterations at one year post‐COVID‐19 is associated with increased serum PD‐L2 levels and altered CD4/CD8 ratio

“…Different studies have demonstrated that specific CD4+ T-cell subsets are necessary to alleviate some interstitial lung damage or maintain IFN-γ production, avoiding senescence-associated pulmonary fibrosis. 30,31 The up-sPD-L2 profile observed in those post-COVID-ILD patients with lung structural and functional alterations could affect other cell subsets; reports indicated that high expression of PD-L2 is related to the presence of a macrophage subpopulation with anti-inflammatory and profibrotic functions called M2, which leads to the inhibition of T-cells, and in tumor models has been described that high expression of PD-L2 is associated with a poor prognosis. 32,33 Several studies suggest that M2 macrophages play a central role in the pathogenesis of fibrosis; for instance, M2 secretes connective tissue growth factors to mediate the proliferation and migration of fibroblasts.…”

“…CD4+ T‐cells are one of the leading players in driving the adaptive immune response, primarily secreting cytokines to regulate or activate other cell subsets. Different studies have demonstrated that specific CD4+ T‐cell subsets are necessary to alleviate some interstitial lung damage or maintain IFN‐γ production, avoiding senescence‐associated pulmonary fibrosis 30,31 …”