This document summarizes a presentation on T-helper 9 (Th9) cells, a relatively new member of the Th cell family. The presentation outlines that Th9 cells differentiate from naive CD4+ T cells in response to TGF-β and IL-4 cytokines. Th9 cells secrete IL-9 and play roles in allergies, parasite expulsion, autoimmune diseases, cancer, and other conditions. While Th9 cells can promote inflammation and tissue damage, they also help expel parasites and inhibit tumor growth. Further research is needed to understand Th9 cell mechanisms and potential immunotherapy applications.

1. Addis Ababa University
Aklilu Lemma Institute Of Pathobiology
Department of Tropical and Infectious Diseases
Mini presentation
on
T-Helper Cell 9: A relatively new member in the Th cell
family.
By
Dr. Tekalign Tadesse (Doctor of Veterinary Medicine)
February, 2020
Addis Ababa, Ethiopia

2. Outlines of Presentation
1. Introduction
2. Differentiation of T cell
3. Cytokines and T Factors for Th-9 cell
4. Protective Role of Th-9 cell
5. Detrimental Role of Th-9 cell
6. Therapeutic role of Th-9 cell
7. Conclusion and a way forward
8. References

3. 1. Introduction
 Unlike that of B lymphocytes, T lymphocytes are originated from
Bone marrow and take their ways to thymus to mature and get
educated.
 Upon recognition of Ag presented by antigen presenting cells
bearing MHC-II, this cell will be differentiated into T-helper cell.
 Naïve CD4+ T-helper cells differentiate into T-helper cell
subsets in the presence, cytokines, co-stimulatory factors and
other factors (Veldhoen et al., 2008).
 Differentiated T helper cells play a myriad of functions in
obliterating the infecting pathogens.
 However, when these cell-mediated responses are not properly
regulated, unrestrained CD4+ T helper cell responses lead to
chronic inflammation and tissue damage.

4. 2. Pathway towards Th-9 differentiation
Mubeccel et al., 2012. Differentiation pathways of CD4+ TH cell
subsets

5. 3. Cytokines and transcription factors
 Differentiating cytokines, TGF-β) and IL-4 promotes the
differentiation into effector Th-9 cells.
 TGF-β signal induce expression of Foxp3 and PU.1
transcription factors, PU.1 directly bind to Il9 gene
promoter.
 IL-4 is secreted from Th-2 cells and mast cells and has
a function of activating the transcription factor STAT6.
 Transcription factors that include;
 STAT6 (signal transducer and activator of transcription
6),
 PU.1, IRF4 (interferon response factor 4), and GATA3
 Th-9 secret prominently IL-9 and other IL-10, IL-21 as
effectors cytokine, involved allergy, autoimmunity, infections,
cancer and immunodeficiency
 However, some cytokines, including IFN-g, IL-12, IL-18 and

6. (Frédérique et al., 2015).Cytokines and transcriptional factor
of TH-9 cell.

7. 4. Role of Th-9 cells
Role in Allergy
• In experimental study in the lungs of transgenic mice,
increased IL-9 expression resulted in airway
inflammation, hypertrophy of epithelial cells, increased
mucus generation (Rukhsana Jabeen et al., 2012).
• Deficiency of Th-9 cell transcription factors, such as
PU.1, IRF4, and BATF, mice developed lower level
inflammatory symptom.
• Serum levels of IL-9 have a moderate positive
correlation with symptom severity including itching,
sneezing, and rhinorrhea in patients with allergic rhinitis
suggesting a role of IL-9 in acute allergic reactions.
• In addition, Th-9 cells was also involved in the effect of

8. Role in Parasite expulsion
 Experimentally mice was infected with nematode Trichuris
muris and given IL-9, and caused eosinophilia, increased
intestinal permeability and contractility, which leads to
parasite expulsion (Rukhsana Jabeen et al., 2012).
 It has been identified that the deficiency of TGF-B in mice is
also associated with impaired IL-9 production, elevated
worm burden and diminished mast cells in the cecum
(Veldhoen et al., 2008).
 In a study Mice were infected by Leishmania major (L.
major), then levels of IL-9 were evaluated. Lymphocytes in
lymph nodes and spleens of L. major-infected produced
higher levels of IL-9 during an acute immune response
(Gesnner et al.,1993) .
 Indeed, adoptive transfer of Th-9 cells into Rag-1 deficient

9. Role in Autoimmune diseases
 High expression of IL-9 were detected in patients with IBD,
especially in those with ulcerative colitis (Weigmann and
Neurath, 2017).
 Th-9 cells play prominent roles in the pathogenesis of
Rheumatoid Arthritis with serum levels of IL-9 being
increased in RA patients compared with healthy controls
(Dantas et al., 2015).
 It has also been revealed that the expression of both the
mRNA and protein of IL-4, and TGF-B are elevated in RA
synovial tissue, indicating a possible role of TH-9 and IL-9
in the development of RA(Ciccia et al., 2015).
 Again increased serum concentrations of mRNA transcripts

10. Role in Tumor diseases
 The high secretion of IL-9 and IL-21 in the tumor bed
activate and attract dendritic cells, mast cells, NK cell, and
CD8 T-cells to mount an antitumor immune response.
 Th-9 cells have anticancer properties via granzyme B
release (Purwaw et al., 2012).
 It has been recently described that Ag-specific Th-9 cells
are able to inhibit squamous cancer (SQC) growth and also
promote apoptosis in both in vivo and in vitro (Miao et al.,
2017).
 Reverse function of IL-9 in promoting human malignant

11. Role in Tuberculosis
The frequency of Th-9 cells detected in tuberculous pleural
effusion increases during Mycobacterium tuberculosis
infection.
Moreover, pleural mesothelial cells, acting as antigen
presenting cells, promote Th-9 cell differentiation by
presenting antigen.
whereas IL-9 promotes the pleural mesothelial cell repairing
(Sabat, 2010).
Role in transplant tolerance
High levels of IL-9 in the tolerant grafts, which boosted the

12. Therapeutic Roles
 Administration of Th-9 cells, as a therapeutic strategy, leads to
stimulation of CD8+ T cells and DCs recruitment into tumor
site, which mediates antitumor immunity.
 Direct administration of Th-9 cells leads to specific homing of
transferred T cells to the tumor site and more cytokine
production compared with systemic injection of IL-21(Vegran et
al., 2015).
 Recombinant IL-21 was investigated in a phase II study of
patients with metastatic melanoma and a 22.5% response rate
was achieved in the first-line treatment(Petrella et al., 2012).
 Th-9 cells promote over expression of anti-apoptotic protein
Bcl-xL and activation of p38, ERK, and STAT5 signaling
pathways in DCs (park et al., 2014).

13. Summary
 Th-9 cells develop in response to combined signal from TGF-
β and IL-4
 Has transcription factors with complex transduction network
including IRF4, PU.1, GATA3.
 Th-9 cells play a notable role in immune responses by the
acquisition of IL-9 production.
 Th-9 cells and IL-9 play harmful roles in the pathogenesis of
asthma and other allergic diseases and in autoimmune
diseases .
 In microbial, parasite infections,TH-9 cells and IL-9 have
broadly protective roles,
 Cell-derived IL-9 suppresses melanoma growth and

14. Unanswered question and the way forward
1. The exact mechanism of action in invivo (Human
disease) is not well elucidated.
2. The exact cross-linkage with other Th subset is not
well described
3. The role of Th-9 cell may not be universal in all
models
 Taken together, various functions and the different
presence of Th-9 cells and IL-9 in the mentioned
diseases, show the need for more studies to approve
the administration of IL-9 and Th-9 cells as an
immuno-therapeutic strategy in different conditions.

15. References (Thanks to Elsevier journals)
1. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, WestendorfA, Buer J, et al. Transforming growth factor-beta
‘repro-grams’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat
Immunol. 2008;9:1341-
2. Rukhsana, J., and Kaplan, M.H. (2012). The symphony of the ninth: the development and function of Th9 cells.
Current Opinion in Immunology, 24: 303–307.
3. Chang, H., Han, L., Jabeen, R., Carotta, S., Nutt, S.L. and Kaplan, M.K. (2009). PU.1 regulates TCR expression
by modulating GATA-3 activity. Journal of Immunology, 183: 4887–4894.
4. Gessner A, Blum H, Röllinghoff M. Differential regulation ofIL-9-expression after infection with Leishmania major
in sus-ceptible and resistant mice. Immunobiology. 1993;189:419---35.
5. Licona-Limón P, Henao-Mejia J, Temann AU, Gagliani N,Licona-Limón I, Ishigame H, et al. Th9 cells drive
hostimmunity against gastrointestinal worm infection. Immunity.2013;39:744---57.
6. B. Weigmann, M.F. Neurath, Th9 cells in inflammatory bowel diseases, Semin. Immunopathol. 39 (2017) 89–95.
7. Dantas AT, Marques CDL, da Rocha Junior LF, CavalcantiMB, Gonc¸alves SMC, Cardoso PRG, et al. Increased
seruminterleukin-9 levels in rheumatoid arthritis and systemic lupuserythematosus: pathogenic role or just an
epiphenomenon? DisMarkers. 2015;2015:519638.
8. Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W,Jiang X, et al. Robust tumor immunity to melanoma
medi-ated by interleukin-9-producing T cells. Nat Med. 2012;18:1248---53.
9. Miao B-P, Zhang R-S, Sun H-J, Yu Y-P, Chen T, Li L-J, et al.Inhibition of squamous cancer growth in a mouse
model byStaphylococcal enterotoxin B-triggered Th9 cell expansion.Cell Mol Immunol. 2017;14:371---9.
10. Merz H, Houssiau F, Orscheschek K, Renauld J-C, Fliedner A,Herin M, et al. Interleukin-9 expression in human
malignantlymphomas: unique association with Hodgkin’s disease andlarge cell anaplastic lymphoma. Blood.
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12. W. Elyaman, E.M. Bradshaw, C. Uyttenhove, V. Dardalhon, A. Awasthi, J. Imitola, et al., IL-9 induces
differentiation of TH17 cells and enhances function of FoxP3 + natural regulatory T cells, Proc. Natl. Acad. Sci.
U. S. A. 106 (2009) 12885–12890.
13. Petrella TM, Tozer R, Belanger K, Savage KJ, Wong R, SmylieM, et al. Interleukin-21 has activity in patients
with metastaticmelanoma: a phase II study. J Clin Oncol. 2012;30:3396---401.
14. Végran F, Apetoh L, Ghiringhelli F. Th9 cells: a novel CD4 T-cell subset in the immune war against cancer.
Cancer Res.2015;75:475---9
15. Park J, Li H, Zhang M, Lu Y, Hong B, Zheng Y, et al.Murine Th9 cells promote the survival of myeloid

16. This is all what I have and Up to my
ability
Thank you !!!