Incell biology,TH9 cells (T helper type 9 cells, CD4+IL-9+IL-13−IFNγ − )are a sub-population ofCD4+T cellsthat produce interleukin-9 (IL-9). They play a role in defense againsthelminth infections,inallergic responses,inautoimmunity,and tumor suppression.

Characterization

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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 ofinterleukin‑9.[1]Besides IL-9, TH9 cells also produceIL-10andIL-21.However, their functions in TH9 cells are still unclear.[2]

Differentation

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Th9 cells can differentiate either from naiveT lymphocytesor 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

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Cytokinesplay a major role in development of TH9 cells. There are many cytokines impacting differentiation of TH9 cells and their production of IL-9 butIL-4andTGF-βare indispensable for their development and polarization.

IL-4andTGF-βare necessary for naive T lymphocytes to differentiate into TH9 cells.[3][4]whileTGF-βalone can switch TH2 cells into TH9 cells.[5][6]

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

IL-1may induce IL-9 in some cases, andIL-33is able to induce IL-9 in T cells generally.[9]GenerallyIL-1 familymembers enhance expression ofIl9gene.[10]

IL-25also induces IL-9 productionin 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

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STAT6,IRF4,GATA3are absolutely required for TH9 cell development[13][14]and other such asPU.1,BATF,NF-κB,NFAT1,STAT5,AP-1contribute to TH9 sub-population commitment and to IL-9 production.

STAT6is 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-3in TH9 cells development represses transcriptional factorFOXP3,which would other wise let to other T helper cell subpopulation.[14]

IRF4binds to the promoter ofIl-9 genein TH9 cells and it is dependent on STAT6.[14]

BATFhas been also shown to bind to theIl-9 genepromoter and to activateIl-9genetranscription.[14]

PU.1works by directly binding to the promoter ofIl-9 geneand attract chromatin-modifying enzymes which reinforceIl9-genetranscription.[5][2]

NF-κBandNFAT1,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 toIl-9 genepromoter, although it has not yet been determined how important this pathway is for TH9 developmentin vitroandin vivo.[19][20]

Molecules with regulatory effects

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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]thenJagged2,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 (TNFRSF4or OX40), andthymic stromal lymphopoietin(TSLP).[22][11][6][23][24][25][26][27]

Physiological functions

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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 inhibitmelanomacell growth,[30][31]increase anti-tumor lymphocytes, and drastically lower tumor mass and disease severity.[29]On the other hand patients sufferinghepatocellular carcinomawith high TH9 infiltration had shorter disease-free survival period after surgical resection.[32]

Pathophysiological functions

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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

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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 ofin vivoIL-9 with serum IgE concentration. The percentages of IL-9-secreting T cells of atopic patients also correlated with serum IgE in adults withasthma.[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

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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

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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

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A higher percentage of TH9 cells in patients with chronicHCVwas linked to higher levels of liver enzymes, more severe disease progression and faster development ofHCC.[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

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