T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are developmentally distinct from Th1 and Th2 cells. They create inflammation and tissue injury in autoimmune disease

1. T helper-17 cells
Jafar Ali
M.Phil 2nd
QUAID-i-AZAM UNIVERSITY
ISLAMABAD

2. Th 17 cells
 T helper 17 cells (Th17) are a subset of T helper cells producing
interleukin 17 (IL-17)
 discovered in 2007.
 distinct from Th1 and Th2 cells
 defence
 play a role in inflammation and tissue injury
 autoimmune disease such as multiple sclerosis
 Rheumatoid arthritis

3. Subset of t cells

4. Th17 cell lineage development
.
RORγT
STAT-3
Naive CD4
APC
Th17
IL-17
IL-22
IL-21
IL23-APC
IL-6
TGF-β
Pre-Th17

5. Th17 Differentiation

6. Steps in the generation of Th17 cells.
The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differen
The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17
differentiation pathway. Th17 cells produce IL-21, which further amplifies Th17 generation
in an autocrine manner. IL-21 also induces the IL-23R on differentiated Th17 cells to make
them responsive to IL-23 signaling. IL-23 stabilizes the Th17 phenotype by secreting IL-
17A, IL-17F and IL-22 and helping Th17 cells to acquire effector functions. h further
amplifies Th17 generati
(Awasthi and Kuchroo, International Immunology, 2009)

7. Transcriptional regulation
 RORᴽt……….. necessary and sufficient to induce IL-17
expression
 ROR∞….. With RORᴽt promotes differntiation of Th 17
cells
 Runx1, to Il17 promoter and RORᴽt will give optimal IL-
17expression in CD4+
 Interleukin regulatory factor 4 (IRF4)….. TH17 induction
 STAT3………… TH17 cell development and function
is also critically dependent

8. Disturbances in the homeostasis of Th17 lymphocytes
in patients with hyper IgE syndrome (HIES) and
chronic granulomatous disease (CGD)
Horvath R.1, Lastovicka J.1, Polouckova A.1, Sedlacek P.2, Bartunkova J.1, Sediva A.1, Spisek R.1
1Department of Immunology, Charles University, 2nd Medical School and Faculty Hospital Motol,
Prague, Czech Republic

9. Th 17 cell functions
 Production of IL-17 cytokines family (IL-17, IL-21, IL-22) which leads to
the chemoattraction of neutrophils
 Accumulating Th17 are highly pro - inflammatory and that Th17 cells
with specificity for self-antigens lead to severe autoimmunity- (psoriasis,
Crohn´s disease, multiple sclerosis)

10.  Initially, from studies in mice, Th17 cells were thought to play an important
role in host defense against extracellular pathogens, which are not
efficiently cleared by Th1-type and Th2- type immunity
 However, identity of pathogens cleared by Th17 was unknown
 Direct evidence for understanding physiological target of Th17 cells came
from studies of patients with mutations in STAT-3, a critical transcription
factor for the differentiation of Th17 cells
Physiological role of Th17 cells in humans

11. Defective Th17 cells in Hyper IgE syndrome
 Primary immunodeficiency
caused by mutations in STAT-3
transcription factor, NEJM 2007
 Dermatitis, boils, cyst-forming
pneumonias, retained primary
dentition, bone abnormalities and
elevated serum IgE levels
 Abnormal and devastating
susceptibility to a narrow spectrum
of infections, most commonly
Staphylococcus aureus and
Candida albicans
 Abrogated numbers of Th17 cells,
Nature 2008, JEM 2008
nonspecific stimulation

12.  Studies in Hyper IgE point to a critical role of Th17 cells in the response
against candidal and staphylococcal infections
 However, there are other diseases with similar spectrum of dominant
pathogens where the characteristics of Th17 have not been tested
 We thus decided to test Th17 cells compartment in chronic granulomatous
disease
Defective Th17 cells in Hyper IgE syndrome

13. Clinical mimicry of HIES with other primary
immunodeficiencies – Chronic granulomatous disease (CGD)
 Primary immunodeficiency
 Mutations in the NADPH oxidase
system
 Profound defect of respiratory burst in
myeloid cells
 Recurrent infections, organ
granulomas
 Dominant susceptibility to
staphylococcal and candidal
infections

14. Aim of the study
 Analyze and compare the characteristics of Th17 compartment in
HIES and CGD patients
Patients and methods
 4 patients from 3 families with HIES
 7 patients with CGD (2 patients underwent allo-BMT)
 Mutations in STAT-3 and NADPH oxidase - genetics
 ELISA

15. 0 10
2
10
3
10
4
10
5
0
10
2
10
3
104
10
5
4.12
0.51
0 10
2
10
3
10
4
10
5
0
10
2
10
3
104
10
5
0.13
1.67
0 10
2
10
3
10
4
10
5
0
10
2
103
104
10
5
2.32
1.98
0 10
2
10
3
10
4
10
5
0
102
103
10
4
10
5
5.91
0.49
0 10
2
10
3
10
4
10
5
0
102
103
10
4
10
5
0.078
3.5
0 10
2
10
3
10
4
10
5
0
10
2
103
104
10
5
1.25
2.87
0 10
2
10
3
10
4
10
5
0
102
103
10
4
10
5
6.51
0.76
0 10
2
10
3
10
4
10
5
0
102
103
10
4
10
5
6.97
0.36
0 10
2
10
3
10
4
10
5
0
102
103
10
4
10
5
1.91
1.55
0
0,5
1
1,5
2
2,5
3
3,5
Controls HIES CGD
%ofIL-17+CD4+cells
0
2
4
6
8
10
12
14
Controls HIES CGD%ofIFNgamma+CD4+cells
IFNgamma-PE
IL-17 A647
Controls HIES CGD
A
B
Results – Th17 numbers in CGD and HIES
p<0,05
p<0,05
p<0,05
p=0,39
p<0,05
p=0,05
• absent Th17 cells in HIES
• high frequencies of Th17 in CGD

16. Results – cytokine production
IL-17
0
200
400
600
800
1000
1200
pg/ml
Controls HIES CGD
A
IL-21
0
500
1000
1500
2000
2500
pg/ml
Controls HIES CGD
p<0,05
p<0,05
p<0,05
p=0,06
p=0,29
p=0,14
IL-23
0
200
400
600
800
1000
1200
pg/ml
Controls HIES CGD
p<0,05
p<0,05
p<0,05
•low levels of IL-17 and IL-21 in HIES
B
•high levels of IL-17 and IL-21 in CGD
•extremely elevated levels of IL-23 in HIES
•elevated levels of IL-23 in CGD
Th17 effector cytokines Polarization cytokine

17. 0 102
103
104
105
0
102
103
104
105
0.84
8.64
0 102
103
104
105
0
102
103
104
105
0.12
1.83
IFNgamma-PE
IL-17 A647
A
Correction of defect in Th17 cells in two CGD patients after
successful BMT
0
,5
1
1,5
2
2,5
3
%ofCD4pos.Tcells
Th17
CGD
HIES
Controls
0
2
4
6
8
10
12
14
%ofCD4pos.Tcells IFN-g
B
p#1
p#2
pre-BMT
pre-BMT
CGD after BMT
• normalized numbers of Th17 cells after BMT
p=0,52
p=0,24
post-BMT
post-BMT

18. Results – cytokine production after allo-BMT
CGD
HIES
Controls
0
200
400
600
800
1000
1200
1400
pg/ml
IL-17
0
250
500
750
1000
1250
1500
1750
2000
pg/ml
IL-21
p=0,24
0
200
400
600
800
1000
pg/ml
IL-23
A Th17 effector cytokines Polarization cytokine
B
pre-BMT
pre-BMT
pre-BMT
CGD after BMT
p=0,33
p=0,12
•decreased production of IL17,21 and 23 after BMT
post-BMT
post-BMT
post-BMT

19. Possible theoretical explanations
Healthy Th17APC
IL-23 IL-17,22,21 etc
Neutro
Lympho
Mono
Eradication
Candida
S.aureus
HIES Th17APC
IL-23 IL-17,22,21 etc
Candida
S.aureus
STAT3 mutation
In-efficient immune cells attraction
Pathogen persistence
CGD Th17APC
IL-23 IL-17,22,21 etc
Neutro
Lympho
Mono
In-efficient eradication
Candida
S.aureus NADPH mutation
Pathogen persistence

20. Conclusions
 We identified disturbances in the homeostasis of Th17 lymphocytes
in HIES and CGD patients
 Absent Th17 cells in STAT-3 deficient HIES patients
 Significantly higher frequencies of Th17 cells in CGD
 Increase of Th17 cells in CGD is likely to be secondary as a result of
defect in neutrophils
 BMT leads to the normalization of elevated Th17 cell numbers and
coresponding IL-17 production
 Positive pro-inflammatory loop caused by Th17 cells contributes to
the formation of granulomas
 These findings confirm the critical role of Th17 lymphocytes in the
elimination of candidal and staphylococcal infections