Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions.
OBJECTIVE
Transforming growth factor-β is considered to play a key role in the process of fibrosis in systemic sclerosis (SSc) and in the development of regulatory T cells (Treg) and pro-inflammatory Th17 T cells producing interleukin 17 (IL-17) and IL-22. The authors therefore postulated that SSc could be characterised by a marked Treg/Th17 imbalance. Previous works did not distinguish between the different subsets of Treg and the non-regulatory FoxP3(+) cells leading to inconsistent results.


METHODS
Combined phenotypic and functional analysis of Th17 cells and FoxP3(+)CD4 T cells, discriminating activated Tregs and resting Tregs from non-regulatory FoxP3(+) T cells, in blood and skin of SSc patients.


RESULTS
In early disease stages, there is a decreased proportion of activated Tregs. A concomitant resting Treg deficit becomes more apparent with disease progression. Active and diffuse forms of the disease are characterised by a relatively higher proportion of all FoxP3(+) subsets, including non-regulatory T cells. No peripheral or local IL-17 amplification was observed. However, the authors found significantly increased IL-22 transcription levels in SSc lesional skin, as compared with healthy skin. Cytofluorometry confirmed the existence in SSc patients and controls of a distinct subset of T cells producing IL-22 in the absence of IL-17.


CONCLUSIONS
SSc pathogenesis does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg defect. Active and diffuse forms of the disease are associated with a FoxP3 signature. Altogether, our data depict a status of regulatory/pro-inflammatory T cell imbalance in SSc.
(INSERM) UMR-S 945, Paris,France.
Alexis
A
Mathian
Christophe
C
Parizot
Karim
K
Dorgham
Salim
S
Trad
Laurent
L
Arnaud
Martin
M
Larsen
Makoto
M
Miyara
Miguel
M
Hié
Jean-Charles
JC
Piette
Camille
C
Frances
Hans
H
Yssel
Zahir
Z
Amoura
Guy
G
Gorochov
D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000097043:Interleukin-22
D015415:Biomarkers; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22; C418974:FOXP3 protein, human