Biology:Th 9 cell

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In cell biology, TH9 cells (T helper type 9 cells, CD4+IL-9+IL-13−IFNγ − ) are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.

Characterization

TH9 cells are characterized by their cell surface expression of CD4 and CCR6 and the lack of CCR4. Additionally, they are defined by their high secretion of interleukin‑9.[1] Besides IL-9, TH9 cells also produce IL-10 and IL-21. However, their functions in TH9 cells are still unclear.[2]

Differentation

Th9 cells can differentiate either from naive T lymphocytes or by a shift from TH2 cells.[3][4] There are numbers of cytokines, transcription factors and other molecules, that have a role in TH9 differentiation.

Cytokines in differentiation

Cytokines play a major role in development of TH9 cells. There are many cytokines impacting differentiation of TH9 cells and their production of IL-9 but IL-4 and TGF-β are indispensable for their development and polarization.

IL-4 and TGF-β are necessary for naive T lymphocytes to differentiate into TH9 cells.[3][4] while TGF-β alone can switch TH2 cells into TH9 cells.[5][6]

IL-2 is critical for interleukin-9 production by TH9 cells.[7][8]

IL-1 may induce IL-9 in some cases, and IL-33 is able to induce IL-9 in T cells generally.[9] Generally IL-1 family members enhance expression of Il9 gene.[10]

IL-25 also induces IL-9 production in vivo.[11]

Development of TH9 cells requires a balanced cytokines signaling for its establishment.[12] All mentioned cytokines then signal through specific transcription factors, which are later on required for a TH9 polarization.

Transcription factors in differentiation

STAT6, IRF4, GATA3 are absolutely required for TH9 cell development[13][14] and other such as PU.1, BATF, NF-κB, NFAT1, STAT5, AP-1 contribute to TH9 sub-population commitment and to IL-9 production.

STAT6 is activated by signaling through IL-4 receptor.[15] Once activated, phosphorylated STAT6 mediate the transcription of Gata3 and Irf4, which are both necessary for polarization of TH9 cells.[16][17] STAT6 repress the expression of transcription factors T-bet and Foxp3 in TH9 cells, that normally block IL-9 production.[14]

GATA-3 in TH9 cells development represses transcriptional factor FOXP3, which would other wise let to other T helper cell subpopulation.[14]

IRF4 binds to the promoter of Il-9 gene in TH9 cells and it is dependent on STAT6.[14]

BATF has been also shown to bind to the Il-9 gene promoter and to activate Il-9gene transcription.[14]

PU.1 works by directly binding to the promoter of Il-9 gene and attract chromatin-modifying enzymes which reinforce Il9-gene transcription.[5][2]

NF-κB and NFAT1, are needed for a TCR-induced interleukin-9 production by TH9 cells.[18]

STAT5, downstream factor of IL-2, induce TH9 cells IL-9. STAT5 directly bind to Il-9 gene promoter, although it has not yet been determined how important this pathway is for TH9 development in vitro and in vivo.[19][20]

Molecules with regulatory effects

Numbers of molecules enhance or dampen IL-9 production and contribute to TH9 development such as:

Activin A that can fully substitute the role of TGF-β in TH9 cells,[21] then Jagged2, programmed cell death ligand (PD-L2), cyclooxy- genase (COX)-2, 1,25-dihydroxyvitamin D3, calcitonin gene-related peptide (CGRP), tumor necrosis factor receptor superfamily member 4 (TNFRSF4 or OX40), and thymic stromal lymphopoietin (TSLP).[22][11][6][23][24][25][26][27]

Physiological functions

The main physiological role of TH9 cells, while poorly defined, is defense against helminthic infections.[28] This is likely mediated by local and/or systemic production of Interleukin-9, as well as promoted survival of other anti-parasitic leukocytes, including mast cells, eosinophils and basophils.[29]

Th9 cells have also shown both pro- and anti-tumorigenic activity, depending on the type of cancer.[29] They have been shown to inhibit melanoma cell growth,[30][31] increase anti-tumor lymphocytes, and drastically lower tumor mass and disease severity.[29] On the other hand patients suffering hepatocellular carcinoma with high TH9 infiltration had shorter disease-free survival period after surgical resection.[32]

Pathophysiological functions

TH9 cells appear to be linked to many pathophysiological processes. Their exact role is poorly understood, as they appear to have a pleiotropic effect and seem to be heavily dependent on the local, as well as systemic, cytokine environment.

Allergies

TH9 cells are present in the peripheral blood of allergic patients while such a population is rare in non-allergic persons.[22] Few studies have reported distinct correlations of in vivo IL-9 with serum IgE concentration. The percentages of IL-9-secreting T cells of atopic patients also correlated with serum IgE in adults with asthma.[22]

Two studies showed that transferred TH9 cells result in allergic inflammation in the lung.[16] It was also observed that TH9 cells can promote intestinal and central nervous system inflammation.[33]

Asthma

TH9 cells are strongly linked to asthma given their presence in draining lymph nodes and airways.[29] TH9-Derived IL-9 has been shown to exacerbate the allergic immune response by enhancing antibody production and increasing cell infiltration inside of the respiratory tract.[29]

Autoimmune inflammation

TH9 cells contribute to ulcerative colitis, due to the cell’s ability to impair cellular repair,[29] as well as due to the ability of secreted IL-9 to promote a TH2-like immune response.[34] This may also play a role in TH9 tumor suppression (see "Physiological functions" above). TH9 have been shown to play a role in both early and progressive phase of multiple sclerosis by decreasing the effects of pro-inflammatory TH17.[35] Increased levels of IL-9, mainly produced by TH9 have been detected in patients in remission phase of the disease.[36] However, in vitro differentiated Th9 have been shown to induce EAE and cause peripheral neuropathies in mice,[37] emphasizing the importance of context in which the cells develops and functions.[38]

Chronic infections

A higher percentage of TH9 cells in patients with chronic HCV was linked to higher levels of liver enzymes, more severe disease progression and faster development of HCC.[39] Also remission and faster HCV clearance was associated with lower TH9 cytokines' levels.[40] This might be caused by TH9 mediated promotion of TH17 phenotype and hindering of TH1 phenotype which leads to persisting viral infection. There were several publications trying to elucidate role of TH9 cells in chronic HBV infection with inconsistent results.[41][42]

References

  1. ↑ Kaplan, Mark H.; Hufford, Matthew M.; Olson, Matthew R. (May 2015). "The development and in vivo function of T helper 9 cells". Nature Reviews. Immunology 15 (5): 295–307. doi:10.1038/nri3824. ISSN 1474-1741. PMID 25848755. 
  2. ↑ 2.0 2.1 Goswami, Ritobrata; Kaplan, Mark H. (2012-09-15). "Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells". Journal of Immunology 189 (6): 3026–3033. doi:10.4049/jimmunol.1201496. ISSN 1550-6606. PMID 22904310. 
  3. ↑ 3.0 3.1 Veldhoen, Marc; Uyttenhove, Catherine; van Snick, Jacques; Helmby, Helena; Westendorf, Astrid; Buer, Jan; Martin, Bruno; Wilhelm, Christoph et al. (December 2008). "Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset". Nature Immunology 9 (12): 1341–1346. doi:10.1038/ni.1659. ISSN 1529-2916. PMID 18931678. 
  4. ↑ 4.0 4.1 Veldhoen, Marc; Uyttenhove, Catherine; van Snick, Jacques; Helmby, Helena; Westendorf, Astrid; Buer, Jan; Martin, Bruno; Wilhelm, Christoph et al. (December 2008). "Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset". Nature Immunology 9 (12): 1341–1346. doi:10.1038/ni.1659. ISSN 1529-2908. PMID 18931678. 
  5. ↑ 5.0 5.1 Chang, Hua-Chen; Sehra, Sarita; Goswami, Ritobrata; Yao, Weiguo; Yu, Qing; Stritesky, Gretta L.; Jabeen, Rukhsana; McKinley, Carl et al. (June 2010). "The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation". Nature Immunology 11 (6): 527–534. doi:10.1038/ni.1867. ISSN 1529-2916. PMID 20431622. 
  6. ↑ 6.0 6.1 Elyaman, Wassim; Bassil, Ribal; Bradshaw, Elizabeth M.; Orent, William; Lahoud, Youmna; Zhu, Bing; Radtke, Freddy; Yagita, Hideo et al. (2012-04-20). "Notch Receptors and Smad3 Signaling Cooperate in the Induction of Interleukin-9-Producing T Cells". Immunity 36 (4): 623–634. doi:10.1016/j.immuni.2012.01.020. ISSN 1074-7613. PMID 22503540. 
  7. ↑ Schmitt, E.; Germann, T.; Goedert, S.; Hoehn, P.; Huels, C.; Koelsch, S.; Kühn, R.; Müller, W. et al. (1994-11-01). "IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma". Journal of Immunology 153 (9): 3989–3996. doi:10.4049/jimmunol.153.9.3989. ISSN 0022-1767. PMID 7930607. 
  8. ↑ Singh, Tej Pratap; Schön, Michael P.; Wallbrecht, Katrin; Gruber-Wackernagel, Alexandra; Wang, Xiao-Jing; Wolf, Peter (2013-01-15). "Involvement of IL-9 in Th17-Associated Inflammation and Angiogenesis of Psoriasis". PLOS ONE 8 (1): e51752. doi:10.1371/journal.pone.0051752. ISSN 1932-6203. PMID 23335955. Bibcode: 2013PLoSO...851752S. 
  9. ↑ Blom, Lars; Poulsen, Britta C.; Jensen, Bettina M.; Hansen, Anker; Poulsen, Lars K. (2011). "IL-33 induces IL-9 production in human CD4+ T cells and basophils". PLOS ONE 6 (7): e21695. doi:10.1371/journal.pone.0021695. ISSN 1932-6203. PMID 21765905. Bibcode: 2011PLoSO...621695B. 
  10. ↑ Guo, Liying; Wei, Gang; Zhu, Jinfang; Liao, Wei; Leonard, Warren J.; Zhao, Keji; Paul, William (2009-08-11). "IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells". Proceedings of the National Academy of Sciences of the United States of America 106 (32): 13463–13468. doi:10.1073/pnas.0906988106. ISSN 1091-6490. PMID 19666510. Bibcode: 2009PNAS..10613463G. 
  11. ↑ 11.0 11.1 Angkasekwinai, Pornpimon; Chang, Seon Hee; Thapa, Manoj; Watarai, Hiroshi; Dong, Chen (March 2010). "Regulation of IL-9 expression by IL-25 signaling". Nature Immunology 11 (3): 250–256. doi:10.1038/ni.1846. ISSN 1529-2916. PMID 20154671. 
  12. ↑ Kaplan, Mark H. (March 2013). "Th9 cells: differentiation and disease". Immunological Reviews 252 (1): 104–115. doi:10.1111/imr.12028. ISSN 0105-2896. PMID 23405898. 
  13. ↑ Dardalhon, Valérie; Awasthi, Amit; Kwon, Hyoung; Galileos, George; Gao, Wenda; Sobel, Raymond A.; Mitsdoerffer, Meike; Strom, Terry B. et al. (December 2008). "IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells". Nature Immunology 9 (12): 1347–1355. doi:10.1038/ni.1677. ISSN 1529-2916. PMID 18997793. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Goswami, Ritobrata; Jabeen, Rukhsana; Yagi, Ryoji; Pham, Duy; Zhu, Jinfang; Goenka, Shreevrat; Kaplan, Mark H. (2012-02-01). "STAT6-dependent regulation of Th9 development". Journal of Immunology 188 (3): 968–975. doi:10.4049/jimmunol.1102840. ISSN 1550-6606. PMID 22180613. 
  15. ↑ Kaplan, M. H.; Schindler, U.; Smiley, S. T.; Grusby, M. J. (March 1996). "Stat6 is required for mediating responses to IL-4 and for development of Th2 cells". Immunity 4 (3): 313–319. doi:10.1016/S1074-7613(00)80439-2. ISSN 1074-7613. PMID 8624821. 
  16. ↑ 16.0 16.1 Staudt, Valérie; Bothur, Evita; Klein, Matthias; Lingnau, Karen; Reuter, Sebastian; Grebe, Nadine; Gerlitzki, Bastian; Hoffmann, Markus et al. (2010-08-27). "Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells". Immunity 33 (2): 192–202. doi:10.1016/j.immuni.2010.07.014. ISSN 1097-4180. PMID 20674401. 
  17. ↑ Zhu, Jinfang; Min, Booki; Hu-Li, Jane; Watson, Cynthia J.; Grinberg, Alex; Wang, Qi; Killeen, Nigel; Urban, Joseph F. et al. (November 2004). "Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses". Nature Immunology 5 (11): 1157–1165. doi:10.1038/ni1128. ISSN 1529-2908. PMID 15475959. 
  18. ↑ Jash, Arijita; Sahoo, Anupama; Kim, Gi-Cheon; Chae, Chang-Suk; Hwang, Ji-Sun; Kim, Jung-Eun; Im, Sin-Hyeog (2012-05-04). "Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-κB (NF-κB)-mediated interleukin-9 (IL-9) transactivation". The Journal of Biological Chemistry 287 (19): 15445–15457. doi:10.1074/jbc.M112.340356. ISSN 1083-351X. PMID 22427656. 
  19. ↑ Fung, Michelle M.; Chu, Yen-Lin; Fink, J. Lynn; Wallace, Anne; McGuire, Kathleen L. (2005-07-07). "IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1". Oncogene 24 (29): 4624–4633. doi:10.1038/sj.onc.1208507. ISSN 0950-9232. PMID 15735688. 
  20. ↑ Schmitt, E.; Germann, T.; Goedert, S.; Hoehn, P.; Huels, C.; Koelsch, S.; Kühn, R.; Müller, W. et al. (1994-11-01). "IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma". Journal of Immunology 153 (9): 3989–3996. doi:10.4049/jimmunol.153.9.3989. ISSN 0022-1767. PMID 7930607. 
  21. ↑ Jones, Carla P.; Gregory, Lisa G.; Causton, Benjamin; Campbell, Gaynor A.; Lloyd, Clare M. (April 2012). "Activin A and TGF-β promote T(H)9 cell-mediated pulmonary allergic pathology". The Journal of Allergy and Clinical Immunology 129 (4): 1000–1010.e3. doi:10.1016/j.jaci.2011.12.965. ISSN 1097-6825. PMID 22277204. 
  22. ↑ 22.0 22.1 22.2 Yao, Weiguo; Zhang, Yanlu; Jabeen, Rukhsana; Nguyen, Evelyn T.; Wilkes, David S.; Tepper, Robert S.; Kaplan, Mark H.; Zhou, Baohua (2013-02-21). "Interleukin-9 is Required for Allergic Airway Inflammation Mediated by the Cytokine Thymic Stromal Lymphopoietin". Immunity 38 (2): 360–372. doi:10.1016/j.immuni.2013.01.007. ISSN 1074-7613. PMID 23376058. 
  23. ↑ Kerzerho, Jerome; Maazi, Hadi; Speak, Anneliese O.; Szely, Natacha; Lombardi, Vincent; Khoo, Bryant; Geryak, Stacey; Lam, Jonathan et al. (2013-04-01). "Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity". The Journal of Allergy and Clinical Immunology 131 (4): 1048–1057.e2. doi:10.1016/j.jaci.2012.09.027. ISSN 0091-6749. PMID 23174661. 
  24. ↑ Li, Hong; Edin, Matthew L.; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Gruzdev, Artiom; Cheng, Jennifer; Dackor, Ryan T. et al. (2013-04-15). "Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB". American Journal of Respiratory and Critical Care Medicine 187 (8): 812–822. doi:10.1164/rccm.201211-2073OC. ISSN 1073-449X. PMID 23449692. 
  25. ↑ Palmer, Matthew T.; Lee, Yun Kyung; Maynard, Craig L.; Oliver, James R.; Bikle, Daniel D.; Jetten, Anton M.; Weaver, Casey T. (2011-01-14). "Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells". The Journal of Biological Chemistry 286 (2): 997–1004. doi:10.1074/jbc.M110.163790. ISSN 1083-351X. PMID 21047796. 
  26. ↑ "Calcitonin Gene-Related Peptide and Cyclic Adenosine 5 '-Monophosphate/Protein Kinase A Pathway Promote IL-9 Production in Th9 Differentiation Process (PDF Download Available)". https://www.researchgate.net/publication/236061769. 
  27. ↑ Xiao, Xiang; Balasubramanian, Savithri; Liu, Wentao; Chu, Xiufeng; Wang, Haibin; Taparowsky, Elizabeth J.; Fu, Yang-Xin; Choi, Yongwon et al. (October 2012). "OX40 signaling favors the induction of TH9 cells and airway inflammation". Nature Immunology 13 (10): 981–990. doi:10.1038/ni.2390. ISSN 1529-2908. PMID 22842344. 
  28. ↑ Veldhoen, Marc; Uyttenhove, Catherine; van Snick, Jacques; Helmby, Helena; Westendorf, Astrid; Buer, Jan; Martin, Bruno; Wilhelm, Christoph et al. (December 2008). "Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset". Nature Immunology 9 (12): 1341–1346. doi:10.1038/ni.1659. ISSN 1529-2908. PMID 18931678. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 Kaplan, Mark H.; Hufford, Matthew M.; Olson, Matthew R. (May 2015). "The Development and in vivo function of TH9 cells". Nature Reviews Immunology 15 (5): 295–307. doi:10.1038/nri3824. PMID 25848755. 
  30. ↑ Goswami, Ritobrata; Kaplan, Mark H. (2011-03-15). "A Brief History of IL-9". The Journal of Immunology 186 (6): 3283–3288. doi:10.4049/jimmunol.1003049. ISSN 0022-1767. PMID 21368237. 
  31. ↑ Noelle, Randolph J.; Nowak, Elizabeth C. (October 2010). "Cellular sources and immune functions of interleukin-9". Nature Reviews Immunology 10 (10): 683–687. doi:10.1038/nri2848. ISSN 1474-1733. PMID 20847745. 
  32. ↑ Tan, Hongwu; Wang, Shuyun; Zhao, Ludong (2017-01-24). "A tumour-promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways" (in en). Clinical and Experimental Pharmacology and Physiology 44 (2): 213–221. doi:10.1111/1440-1681.12689. ISSN 0305-1870. PMID 27797409. 
  33. ↑ Kaplan, Mark H. (2013-03-01). "Th9 cells: differentiation and disease". Immunological Reviews 252 (1): 104–115. doi:10.1111/imr.12028. ISSN 1600-065X. PMID 23405898. 
  34. ↑ Vyas Shachi Pranjal, Goswami Ritobrata (2018). "A Decade of Th9 Cells: Role of Th9 Cells in Inflammatory Bowel Disease". Frontiers in Immunology 9: 1139. doi:10.3389/fimmu.2018.01139. PMID 29881387. 
  35. ↑ Ruocco, Gabriella; Rossi, Silvia; Motta, Caterina; Macchiarulo, Giulia; Barbieri, Francesca; Bardi, Marco De; Borsellino, Giovanna; Finardi, Annamaria et al. (2015-08-01). "T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis" (in en). Clinical Science 129 (4): 291–303. doi:10.1042/CS20140608. ISSN 0143-5221. PMID 25700150. 
  36. ↑ Matsushita, Takuya; Tateishi, Takahisa; Isobe, Noriko; Yonekawa, Tomomi; Yamasaki, Ryo; Matsuse, Dai; Murai, Hiroyuki; Kira, Jun-Ichi (2013). "Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis". PLOS ONE 8 (4): e61835. doi:10.1371/journal.pone.0061835. ISSN 1932-6203. PMID 23637915. Bibcode: 2013PLoSO...861835M. 
  37. ↑ Dardalhon, Valérie; Awasthi, Amit; Kwon, Hyoung; Galileos, George; Gao, Wenda; Sobel, Raymond A; Mitsdoerffer, Meike; Strom, Terry B et al. (2008-11-09). "IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3− effector T cells" (in En). Nature Immunology 9 (12): 1347–1355. doi:10.1038/ni.1677. ISSN 1529-2908. PMID 18997793. 
  38. ↑ Elyaman, Wassim; Khoury, Samia J. (2016-11-14). "Th9 cells in the pathogenesis of EAE and multiple sclerosis" (in en). Seminars in Immunopathology 39 (1): 79–87. doi:10.1007/s00281-016-0604-y. ISSN 1863-2297. PMID 27844107. 
  39. ↑ Ali, Mohamed E.; El-Badawy, Omnia; Afifi, Noha A.; Eldin, Abeer Sharaf; Hassan, Elham Ahmed; Halby, Hamada M.; El-Mokhtar, Mohamed Ahmed (2018-06-24). "Role of T-Helper 9 Cells in Chronic Hepatitis C-Infected Patients" (in en). Viruses 10 (7): 341. doi:10.3390/v10070341. PMID 29937515. 
  40. ↑ Guzmán-Fulgencio, María; Jiménez, Jose Luis; Berenguer, Juan; Fernández-Rodríguez, Amanda; López, Juan Carlos; Cosín, Jaime; Miralles, Pilar; Micheloud, Dariela et al. (May 2012). "Plasma IL-6 and IL-9 predict the failure of interferon-α plus ribavirin therapy in HIV/HCV-coinfected patients". The Journal of Antimicrobial Chemotherapy 67 (5): 1238–1245. doi:10.1093/jac/dkr595. ISSN 1460-2091. PMID 22294644. 
  41. ↑ Cui, Meilan; Lv, Ying; Lu, Jianhua; Zhang, Wei; Duan, Yuanyuan; Huang, Yan; Yang, Lei; Li, Man et al. (2017-05-08). "Decreased frequency of circulating Th9 cells in patients with chronic hepatitis B infection" (in en). Journal of Clinical Laboratory Analysis 32 (2): e22246. doi:10.1002/jcla.22246. ISSN 0887-8013. PMID 28481430. 
  42. ↑ Yu, Xueping; Zheng, Yijuan; Deng, Yong; Li, Julan; Guo, Ruyi; Su, Milong; Ming, Desong; Lin, Zhenzhong et al. (April 2016). "Serum Interleukin (IL)-9 and IL-10, but not T-Helper 9 (Th9) Cells, are Associated With Survival of Patients With Acute-on-Chronic Hepatitis B Liver Failure". Medicine 95 (16): e3405. doi:10.1097/md.0000000000003405. ISSN 0025-7974. PMID 27100428. 



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