| Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium tuberculosis(M.tb)that is closely associated with the immune response.It is one of the public health problems that jeopardize global human health.The 2020 global TB report,which is issued by WHO,estimated that the global population with latent TB infection is close to 2 billion,with 9.96 million new TB patients and 1.40 million deaths globally in 2019.M.tb mainly causes the innate immune response and delays type hypersensitivity reaction of the host through respiratory tract invading the lung tissue.Tuberculosis granuloma is the hallmark of tuberculosis,which is characterized by the infiltration of macrophages and T cells at the site of infection in the lung parenchyma.The histopathological damage structure composed of other inflammatory cells collectively encapsulating M.tb.The migration of immune cells inside and outside of granulomas and changes in tissue architecture,are regulated by various types of cytokines,chemokines,and many immunomodulatory factors such as free host molecules.These immunomodulatory factors play an important role in the immunopathology,or perhaps immune protection on TB.According to the literature,the formation of blood vessel like structures around the pathological structures of tuberculosis plays a vital role in the development of tuberculosis,but the mechanism underlying is still not clear yet.Angiopoietin-2(Ang-2)is a cell secreting growth factor involved in immune response.It can enhance vascular permeability,vascular leakage and migration of immune cells.It has reported that Ang-2 may play as a double-edged sword during the infection and inflammation,either promoting pathogenesis or inhibiting immune responses.In our study,we found that Ang-2 was highly expressed in peripheral blood of patients with tuberculosis.Meanwhile,immunofluorescence technique was used to visually detect the expression of Ang-2 in damaged lung of patients with pulmonary tuberculosis,indicating that Ang-2 may be related to the pathogenesis of tuberculosis.To further decipher the immune function of Ang-2,we successfully constructed an Ang-2 gene knockout mouse.Unexpected,the proportion of CD8+T and CD4+T cells was significantly reduced in spleen tissues of Ang-2 deficient mice compared to wild type mice by flow cytometry assay.To understand the immune cell distribution and constructure,single-cell RNA sequencing analysis of lung tissues was performed in Ang-2 deficient mice and WT mice.Data revealed the lack of Ang-2 lead to a decrease in the proportion of T cells in the lungs of Ang-2 deficient mice compared with wild type mice,especially lg ? c-/-cells.Subsequently,we analyzed the different gene expression in these T cells from Ang-2 knockout mice and wild type mice.Data revealeda high expression of Bhlhe40 in lung T cell subsets in mice with Ang2 gene deficiency compared to WT mice.Bhlhe40 is a transcription factor involved in mitochondrial oxidative respiration,which can enhance IFN-y production and regulate resident CD8+T cell fitness and functionality.We subsequently performed cell activation experiments,which showed that CD8+T,CD4+T cells from Ang-2 deficient mice indeed showed increased secretion of cytokines such as IFN-? after stimulation with anti-CD3 and anti-CD28 antibodies.Finally,we established a TB infection murine mode.We found that Ang-2 deficient mice died,and in vivo data presented that the bacterial load of Ang-2 lung conditional knockout mice increased significantly compared with normal mice,showing a more serious pathological damage after 4 weeks of H37Rv infection.Summarily,our results indicate that Ang-2 is involved in the pathogenesis of tuberculosis and has potential immunological functions in the differentiation of T cells and secretion of cytokines.Ang-2 may be involved in inhibiting the immunopathological damage of tuberculosis in the early stage of Mycobacterium tuberculosis infection.Our results provide new insights into elucidating the immune mechanism of anti-tuberculosis. |
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