ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway
BackgroundMaintenance immunosuppression is required for suppression of alloimmunity or allograft rejection. However, continuous use of immunosuppressants may lead to various side effects, necessitating the use of alternative immunosuppressive drugs. The early secreted antigenic target of 6 kDa (ESAT...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1529226/full |
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| author | Xiaofei Huang Xiaofei Huang Yuqun Zeng Jingru Lin Huazhen Liu Huazhen Liu Chun-Ling Liang Chun-Ling Liang Yuchao Chen Yuchao Chen Feifei Qiu Feifei Qiu Jonathan S. Bromberg Zhenhua Dai Zhenhua Dai |
| author_facet | Xiaofei Huang Xiaofei Huang Yuqun Zeng Jingru Lin Huazhen Liu Huazhen Liu Chun-Ling Liang Chun-Ling Liang Yuchao Chen Yuchao Chen Feifei Qiu Feifei Qiu Jonathan S. Bromberg Zhenhua Dai Zhenhua Dai |
| author_sort | Xiaofei Huang |
| collection | DOAJ |
| description | BackgroundMaintenance immunosuppression is required for suppression of alloimmunity or allograft rejection. However, continuous use of immunosuppressants may lead to various side effects, necessitating the use of alternative immunosuppressive drugs. The early secreted antigenic target of 6 kDa (ESAT-6) is a virulence factor and immunoregulatory protein of mycobacterium tuberculosis (Mtb), which alters host immunity through dually regulating development or activation of various immune cells. ESAT-6 may be a potential alternative immunosuppressant that could be utilized to suppress allograft rejection although it remains unknown whether ESAT-6 actually regulates alloimmunity.MethodsIn this study, murine skin or heart allotransplantation was performed to determine the effects of ESAT-6 protein on allograft survival. Flow cytometric analyses were conducted to quantify CD4+Foxp3+ Tregs, while immunohistochemistry was carried out to observe allograft immunopathology. Western blotting was used to detect IĸBα/c-Rel signaling during Treg induction. Finally, CD4+CD25- conventional T cells were cultured to induce Tregs and their proliferation.ResultsHere we found that ESAT-6 significantly extended murine skin and heart allograft survival, alleviated CD3+ T cell infiltration and increased Foxp3+ Tregs in an allograft. ESAT-6 augmented the percentage of CD4+Foxp3+ Tregs, whereas it decreased the frequency of Th1 and CD4+/CD8+ effector T cells in spleen and lymph nodes (LNs) posttransplantation. ESAT-6 also induced CD4+Foxp3+ Tregs from CD4+CD25- T cells in vitro by activating IĸBα/c-Rel signaling pathway, whereas inhibition of c-Rel signaling blocked Treg induction. Moreover, it suppressed conventional CD4+CD25- T cell proliferation in vitro in the absence of antigen-presenting cells (APCs), with an increase in IL-10 and decrease in IFN-γ production. On the other hand, it did not significantly alter DC maturation after allotransplantation.ConclusionThus, ESAT-6 suppresses alloimmunity and inhibits allograft rejection by inducing CD4+Foxp3+ Tregs through IĸBα/c-Rel signaling pathway. |
| format | Article |
| id | doaj-art-3b46dc3343af46a58400d9a83c1ea2e8 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-3b46dc3343af46a58400d9a83c1ea2e82025-01-09T06:10:38ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15292261529226ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathwayXiaofei Huang0Xiaofei Huang1Yuqun Zeng2Jingru Lin3Huazhen Liu4Huazhen Liu5Chun-Ling Liang6Chun-Ling Liang7Yuchao Chen8Yuchao Chen9Feifei Qiu10Feifei Qiu11Jonathan S. Bromberg12Zhenhua Dai13Zhenhua Dai14Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaDepartment of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaSection of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaSection of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaSection of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaSection of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaKidney and Pancreas Transplantation, Department of Surgery and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United StatesSection of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaImmunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, ChinaBackgroundMaintenance immunosuppression is required for suppression of alloimmunity or allograft rejection. However, continuous use of immunosuppressants may lead to various side effects, necessitating the use of alternative immunosuppressive drugs. The early secreted antigenic target of 6 kDa (ESAT-6) is a virulence factor and immunoregulatory protein of mycobacterium tuberculosis (Mtb), which alters host immunity through dually regulating development or activation of various immune cells. ESAT-6 may be a potential alternative immunosuppressant that could be utilized to suppress allograft rejection although it remains unknown whether ESAT-6 actually regulates alloimmunity.MethodsIn this study, murine skin or heart allotransplantation was performed to determine the effects of ESAT-6 protein on allograft survival. Flow cytometric analyses were conducted to quantify CD4+Foxp3+ Tregs, while immunohistochemistry was carried out to observe allograft immunopathology. Western blotting was used to detect IĸBα/c-Rel signaling during Treg induction. Finally, CD4+CD25- conventional T cells were cultured to induce Tregs and their proliferation.ResultsHere we found that ESAT-6 significantly extended murine skin and heart allograft survival, alleviated CD3+ T cell infiltration and increased Foxp3+ Tregs in an allograft. ESAT-6 augmented the percentage of CD4+Foxp3+ Tregs, whereas it decreased the frequency of Th1 and CD4+/CD8+ effector T cells in spleen and lymph nodes (LNs) posttransplantation. ESAT-6 also induced CD4+Foxp3+ Tregs from CD4+CD25- T cells in vitro by activating IĸBα/c-Rel signaling pathway, whereas inhibition of c-Rel signaling blocked Treg induction. Moreover, it suppressed conventional CD4+CD25- T cell proliferation in vitro in the absence of antigen-presenting cells (APCs), with an increase in IL-10 and decrease in IFN-γ production. On the other hand, it did not significantly alter DC maturation after allotransplantation.ConclusionThus, ESAT-6 suppresses alloimmunity and inhibits allograft rejection by inducing CD4+Foxp3+ Tregs through IĸBα/c-Rel signaling pathway.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1529226/fulltransplantationESAT-6alloimmunityregulatory T cell (Treg)immunoregulation |
| spellingShingle | Xiaofei Huang Xiaofei Huang Yuqun Zeng Jingru Lin Huazhen Liu Huazhen Liu Chun-Ling Liang Chun-Ling Liang Yuchao Chen Yuchao Chen Feifei Qiu Feifei Qiu Jonathan S. Bromberg Zhenhua Dai Zhenhua Dai ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway Frontiers in Immunology transplantation ESAT-6 alloimmunity regulatory T cell (Treg) immunoregulation |
| title | ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway |
| title_full | ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway |
| title_fullStr | ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway |
| title_full_unstemmed | ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway |
| title_short | ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway |
| title_sort | esat 6 protein suppresses allograft rejection by inducing cd4 foxp3 regulatory t cells through iκbα crel pathway |
| topic | transplantation ESAT-6 alloimmunity regulatory T cell (Treg) immunoregulation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1529226/full |
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