T细胞耗竭在结核分枝杆菌感染中的作用
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摘要
机体感染结核分枝杆菌(MTB)后,由T细胞介导的细胞免疫在控制MTB感染中起关键作用。然而,在慢性MTB或病毒感染或肿瘤疾病中,T细胞持续大量接触抗原后,会出现T细胞耗竭的状态。T细胞耗竭表现为:T细胞增殖能力及细胞因子分泌水平呈渐进性下降,一些抑制性受体水平逐渐升高[如程序性死亡受体-1(PD-1)]。近期的文献研究表明,T细胞耗竭与机体对MTB感染的无效控制存在关联,在MTB的持续或潜伏感染的发展中可能起重要作用。因此,进一步探索T细胞耗竭在MTB持续感染中的作用及其机制,可能有助于找到潜在的治疗靶点。
After infection with MTB, T lymphocyte-mediated cellular immunity plays a pivotal role in protection against MTB infection. However, under condition of chronic infection with MTB or virus or in the state of tumor diseases, effector T lymphocytes progressively develop to exhaustion state(called T cell exhaustion) upon continuous contact with excessive specific antigens derived from MTB, virus, or tumor cells. Exhausted T cells progressively lose robust functions of cytokine secretion and proliferation, and express multiple inhibitory receptors, such as PD-1. Recent studies revealed that T cell exhaustion seemed to be correlated with inefficient control of MTB infection, and may play an important role in the development of persistent or chronic MTB infection. Thus, further exploring the potential effect of T cell exhaustion on the development of tuberculosis and elucidating the underlying mechanisms may help to reveal new therapeutic targets for persisting MTB infection.
After infection with MTB, T lymphocyte-mediated cellular immunity plays a pivotal role in protection against MTB infection. However, under condition of chronic infection with MTB or virus or in the state of tumor diseases, effector T lymphocytes progressively develop to exhaustion state(called T cell exhaustion) upon continuous contact with excessive specific antigens derived from MTB, virus, or tumor cells. Exhausted T cells progressively lose robust functions of cytokine secretion and proliferation, and express multiple inhibitory receptors, such as PD-1. Recent studies revealed that T cell exhaustion seemed to be correlated with inefficient control of MTB infection, and may play an important role in the development of persistent or chronic MTB infection. Thus, further exploring the potential effect of T cell exhaustion on the development of tuberculosis and elucidating the underlying mechanisms may help to reveal new therapeutic targets for persisting MTB infection.
引文
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[35] Trautmann L,Janbazian L,Chomont N,et al.Upregulation of PD-1 expression on HIV-specific CD8p T-cells leads to reversible immune dysfunction[J].Nat Med,2006,12(10):1198-1202.
[36] Reiley WW,Shafiani S,Wittmer ST,et al.Distinct functions of antigen-specific CD4 T-cells during murine Mycobacterium tuberculosis infection[J].Proc Natl Acad Sci USA,2010,107(45):19408-19413.
[37] Togashi Y,Shitara K,Nishikawa H.Regulatory T cells in cancer immunosuppression-implications for anticancer therapy[J].Nat Rev Clin Oncol,2019,doi:10.1038/s41571-019-0175-7.
[38] Alcazer V,Bonaventura P,Tonon L,et al.Neoepitopes-based vaccines:challenges and perspectives[J].Eur J Cancer,2019,108:55-60.
[39] Sada-Ovalle I,Ocana-Guzman R,Perez-Patrigeon S,et al.Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients[J].J Int AIDS Soc,2015,18:20078.
[40] Ma Z,Zhang E,Yang D,et al.Contribution of Toll like re-ceptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses[J].Cell Mol Immunol,2015,12(3):273-282.
[41] Dowling JK,Mansell A.Toll-like receptors:the swiss army knife of immunity and vaccine development[J].Clin Transl Immunology,2016,5(5):e85.
[42] Prusa J,Zhu DX,Stallings CL.The stringent response and Mycobacterium tuberculosis pathogenesis[J].Pathog Dis,2018,76(5).doi:10.1093/femspd/fty054.
[2] Fletcher HA.Systems approaches to correlates of protection and progression to TB disease[J].Semin Immunol,2018,39:81-87.
[3] Jasenosky LD,Scriba TJ,Hanekom WA,et al.T cells and adaptive immunity to Mycobacterium tuberculosis in humans[J].Immunol Rev,2015,264(1):74-87.
[4] Brighenti S,Andersson J.Local immune responses inhuman tuberculosis:learning from the site of infection[J].J Infect Dis,2012,205(Suppl 2):S316-S324.
[5] Kirman JR,Henao-Tamayo MI,Agger EM.The memory immune response to tuberculosis[J].Microbiol Spectr,2016,4(6):doi:10.1128/microbiolspec.TBTB2-0009-2016.
[6] Scriba TJ,Coussens AK,Fletcher HA.Human immunology of tuberculosis[J].Microbiol Spectr,2016,4(4):doi:10.1128/microbiolspec.TBTB2-0016-2016.
[7] Wherry EJ,Kurachi M.Molecular and cellular insights into T cell exhaustion[J].Nat Rev Immunol,2015,15(8):486-499.
[8] Buchwald ZS,Wynne J,Nasti TH,et al.Radiation,immune checkpoint blockade and the abscopal effect:a critical review on timing,dose and fractionation[J].Front Oncol,2018,8:612.
[9] Abdel-Hakeem MS.Viruses teaching immunology:role of LCMV model and human viral infections in immunological discoveries[J].Viruses,2019,11(2):E106.
[10] Wolchok JD,Kluger H,Callahan MK,et al.Nivolumab plus ipilimumab in advanced melanoma[J].N Engl J Med,2013,369(2):122-133.
[11] Butler NS,Moebius J,Pewe LL,et al.Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection[J].Nat Immunol,2011,13(2):188-195.
[12] Jenkins MK,Khoruts A,Ingulli E,et al.In vivo activation of antigen-specific CD4 T-cells[J].Annu Rev Immunol,2001,19:23-45.
[13] Day CL,Moshi ND,Abrahams DA,et al.Patients with tuberculosis disease have Mycobacterium tuberculosis-specific CD8 T-cells with a pro-apoptotic phenotype and impaired proliferative capacity,which is not restored following treatment[J].PLoS One,2014,9(4):e94949.
[14] Jayaraman P,Jacques MK,Zhu C,et al.TIM3 mediates T-cell exhaustion during Mycobacterium tuberculosis infection[J].PLoS Pathog,2016,12(3):e1005490.
[15] Jurado JO,Alvarez IB,Pasquinelli V,et al.Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T-cell effector functions during human tuberculosis[J].J Immunol,2008,181(1):116-125.
[16] Sakai S,Kawamura I,Okazaki T,et al.PD-1-PD-L1pathway impairs T(h)1 immune response in the late stage of infection with Mycobacterium bovis bacillus calmette-guerin[J].Int Immunol,2010,22(12):915-925.
[17] Wang X,Cao Z,Jiang J,et al.Elevated expression of Tim-3 on CD8 T-cells correlates with disease severity of pulmonary tuberculosis[J].J Infect,2011,62(4):292-300.
[18] Cooper AM,Dalton DK,Stewart TA,et al.Disseminated tuberculosis in interferon gamma gene-disrupted mice[J].J Exp Med,1993,178(6):2243-2247.
[19] Flynn JL,Chan J,Triebold KJ,et al.An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection[J].J Exp Med,1993,178(6):2249-2254.
[20] Ottenhoff TH,Kumararatne D,Casanova JL.Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria[J].Immunol Today,1998,19(11):491-494.
[21] Serbina NV,Lazarevic V,Flynn JL.CD4+ T-cells are requi-red for the development of cytotoxic CD8+ T-cells during Mycobacterium tuberculosis infection[J].J Immunol,2001,167(12):6991-7000.
[22] Chodisetti SB,Gowthaman U,Rai PK,et al.Triggering through Toll-like receptor 2 limits chronically stimulated T-helper type 1 cells from undergoing exhaustion[J].J Infect Dis,2015,211(3):486-496.
[23] Day CL,Abrahams DA,Lerumo L,et al.Functional capacity of Mycobacterium tuberculosis-specific T-cell responses in humans is associated with mycobacterial load[J].J Immunol,2011,187(5):2222-2232.
[24] Coppola M,Ottenhoff TH.Genome wide approaches discover novel Mycobacterium tuberculosis antigens as correlates of infection,disease,immunity and targets for vaccination[J].Semin Immunol,2018,39:88-101.
[25] Crawford A,Angelosanto JM,Kao C,et al.Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection[J].Immunity,2014,40(2):289-302.
[26] Paley MA,Kroy DC,Odorizzi PM,et al.Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection[J].Science,2012,338(6111):1220-1225.
[27] Blackburn SD,Shin H,Haining WN,et al.Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection[J].Nat Immunol,2009,10(1):29-37.
[28] Blackburn SD,Shin H,Freeman GJ,et al.Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade[J].Proc Natl Acad Sci U S A,2008,105(39):15016-15021.
[29] Sakuishi K,Apetoh L,Sullivan JM,et al.Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity[J].J Exp Med,2010,207(10):2187-2194.
[30] Singh A,Mohan A,Dey AB,Mitra DK.Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon c-producing T-cells from apoptosis in patients with pulmonary tuberculosis T-cells[J].J Infect Dis,2013,208:603-615.
[31] Hassan SS,Akram M,King EC,et al.PD-1,PD-L1 and PD-L2 gene expression on T-cells and natural killer cells declines in conjunction with a reduction in PD-1 protein during the intensive phase of tuberculosis treatment[J].PLoS One,2015,10(9):e0137646.
[32] Barber DL,Mayer-Barber KD,Feng CG,et al.CD4T-cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition[J].J Immunol,2011,186(3):1598-1607.
[33] Chen Y,Wu S,Guo G,et al.Programmed death (PD)-1-de-ficient mice are extremely sensitive to murine hepatitis virus strain-3 (MHV-3) infection[J].PLoS Pathog,2011,7(7):e1001347.
[34] Tousif S,Singh Y,Prasad DV,et al.(2011).T-cells from programmed death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection[J].PLoS One,2011,6(5):e19864.
[35] Trautmann L,Janbazian L,Chomont N,et al.Upregulation of PD-1 expression on HIV-specific CD8p T-cells leads to reversible immune dysfunction[J].Nat Med,2006,12(10):1198-1202.
[36] Reiley WW,Shafiani S,Wittmer ST,et al.Distinct functions of antigen-specific CD4 T-cells during murine Mycobacterium tuberculosis infection[J].Proc Natl Acad Sci USA,2010,107(45):19408-19413.
[37] Togashi Y,Shitara K,Nishikawa H.Regulatory T cells in cancer immunosuppression-implications for anticancer therapy[J].Nat Rev Clin Oncol,2019,doi:10.1038/s41571-019-0175-7.
[38] Alcazer V,Bonaventura P,Tonon L,et al.Neoepitopes-based vaccines:challenges and perspectives[J].Eur J Cancer,2019,108:55-60.
[39] Sada-Ovalle I,Ocana-Guzman R,Perez-Patrigeon S,et al.Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients[J].J Int AIDS Soc,2015,18:20078.
[40] Ma Z,Zhang E,Yang D,et al.Contribution of Toll like re-ceptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses[J].Cell Mol Immunol,2015,12(3):273-282.
[41] Dowling JK,Mansell A.Toll-like receptors:the swiss army knife of immunity and vaccine development[J].Clin Transl Immunology,2016,5(5):e85.
[42] Prusa J,Zhu DX,Stallings CL.The stringent response and Mycobacterium tuberculosis pathogenesis[J].Pathog Dis,2018,76(5).doi:10.1093/femspd/fty054.