Th 9 cell

In

T_H9 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, T_H9 cells also produce IL-10 and IL-21. However, their functions in T_H9 cells are still unclear.^[2]

Differentation

Th9 cells can differentiate either from naive T lymphocytes or by a shift from T_H2 cells.^[3][4] There are numbers of cytokines, transcription factors and other molecules, that have a role in T_H9 differentiation.

Cytokines in differentiation

Cytokines play a major role in development of T_H9 cells. There are many cytokines impacting differentiation of T_H9 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 T_H9 cells.^[3][4] while TGF-β alone can switch T_H2 cells into T_H9 cells.^[5][6]

IL-2 is critical for interleukin-9 production by T_H9 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 T_H9 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 T_H9 polarization.

Transcription factors in differentiation

STAT6, IRF4, GATA3 are absolutely required for T_H9 cell development^[13][14] and other such as PU.1, BATF, NF-κB, NFAT1, STAT5, AP-1 contribute to T_H9 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 T_H9 cells.^[16][17] STAT6 repress the expression of transcription factors T-bet and Foxp3 in T_H9 cells, that normally block IL-9 production.^[14]

GATA-3 in T_H9 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 T_H9 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 T_H9 cells.^[18]

STAT5, downstream factor of IL-2, induce T_H9 cells IL-9. STAT5 directly bind to Il-9 gene promoter, although it has not yet been determined how important this pathway is for T_H9 development in vitro and in vivo.^[19][20]

Molecules with regulatory effects

Numbers of molecules enhance or dampen IL-9 production and contribute to T_H9 development such as:

Activin A that can fully substitute the role of TGF-β in T_H9 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 T_H9 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 T_H9 infiltration had shorter disease-free survival period after surgical resection.^[32]

Pathophysiological functions

T_H9 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

T_H9 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 T_H9 cells result in allergic inflammation in the lung.^[16] It was also observed that T_H9 cells can promote intestinal and central nervous system inflammation.^[33]

Asthma

T_H9 cells are strongly linked to asthma given their presence in draining lymph nodes and airways.^[29] T_H9-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

T_H9 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 T_H2-like immune response.^[34] This may also play a role in T_H9 tumor suppression (see "Physiological functions" above). T_H9 have been shown to play a role in both early and progressive phase of multiple sclerosis by decreasing the effects of pro-inflammatory T_H17.^[35] Increased levels of IL-9, mainly produced by T_H9 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 T_H9 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 T_H9 cytokines' levels.^[40] This might be caused by T_H9 mediated promotion of T_H17 phenotype and hindering of T_H1 phenotype which leads to persisting viral infection. There were several publications trying to elucidate role of T_H9 cells in chronic HBV infection with inconsistent results.^[41][42]

References