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Interleukin-10 Producing T-lymphocytes Attenuate Dermal Fibrosis
*Walker D Short, *Xinyi Wang, *Hui Li, *Ling Yu, *Aditya Kaul, *Swathi Balaji, Sundeep G Keswani
Baylor College of Medicine, Houston, TX

OBJECTIVE(S):
CD4+ T-lymphocytes are essential in regulating dermal fibrosis. Regulatory T-lymphocyte(Treg) and Type-1 regulatory T-lymphocyte(Tr1) subsets of the CD4+ T-lymphocytes are potent producers of IL-10, an anti-inflammatory cytokine that we have shown to promote regenerative tissue repair. However, the role of Treg/Tr1 in scarring is unclear. We therefore hypothesize that IL-10 producing CD4+ T-lymphocyte subsets can attenuate dermal wound fibrosis.
METHODS:
C57BL/6J murine(female;6-10wk) splenocytes were enriched for CD4+ cells and sorted into IL-10 producing subsets(Treg;Tr1). In vitro, dermal fibroblasts were co-cultured with Treg or Tr1, and expression of fibrotic(Col-1A, a-SMA), ECM remodeling(Hyaluronan synthases(HAS)1-3) and inflammatory(IL-13Ra2) markers was analyzed at 24h(qRT-PCR). In vivo, 106 total lymphocytes, CD4+, Treg, or Tr1 cells were adoptively transferred into SCID mice that received 6mm bilateral dorsal full-thickness wounds. Wounds and spleens were harvested at days 7,28. Graft uptake, wound closure(H&E) and fibrosis(trichrome) were analyzed.
RESULTS:
Elevated production of IL-10 from Treg(1,918-pg/ml) and Tr1(1,164-pg/ml) was confirmed by ELISA. Fibroblast expression of Col-1A was reduced by 52.4% and 43.5%, and a-SMA was reduced by 25.2% and 44.7%, when co-cultured with Tr1 and Treg respectively. Expression of HAS2, implicated in regeneration, increased 3.11-fold and 2.95-fold; and IL-13Ra2 increased 3.66-fold and 1.94-fold with Tr1 and Treg respectively. Amongst all, adoptive transfer of Tr1 resulted in expedited wound closure wounds at d7 with reduced fibrosis at d28.
CONCLUSIONS:
IL-10 producing T-lymphocytes regulate ECM deposition and inflammatory cytokine balance to attenuate fibrosis. Promoting Tr1 recruitment and IL-10 production in wounds may be a therapeutic target for to promote regenerative wound healing.


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