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

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  • 作者：Chen H, Wang Q, Li J, Li Y, Chen A, Zhou J, Zhao J, Mao Z, Zhou Z, Zhang J, Wang Y, Wang R, Li Q, Zhang Y, Jiang R, Miao D, Jin J
  • 期刊：Aging and Disease
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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 (T EM ) cells in the aged lung. This study also found that physiological aging increased pulmonary CD4 + T EM cells, IFNγ was produced mainly by CD4 + T EM 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 + T EM cells promoted the epithelial-to-mesenchymal transition by activating TIME signaling and cell senescence of AT2 cells with aging. Accumulated IRF1 + CD4 + T EM 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 + T EM cells in physiologically aged lungs could be a therapeutic target for preventing SAPF.

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