Interleukin-10 Producing T Lymphocytes Attenuate Dermal Scarring

Abstract

Objective: Demonstrate the impact of IL-10 producing T lymphocytes on mediating dermal scarring. Summary Background Data: We demonstrated that CD4 + cells are essential to improving postinjury wound healing and preventing fibrosis. CD4 + subsets secrete differential cytokine and growth factor profiles, though their role in fibrosis is not known. IL-10, a key anti-inflammatory cytokine shown to promote regenerative wound healing, is secreted by some CD4 + subsets. We, therefore, hypothesize that IL-10 producing CD4 + T lymphocyte subsets selectively attenuate dermal wound fibrosis. Methods: IL-10 -/- and wild-type murine splenocytes were enriched for CD4 + lymphocytes and adoptively transferred into severe combined immunodeficient (SCID) mice that received full-thickness wounds which were analyzed at days 7 and 28 for inflammation and collagen content. We then sorted CD4 + CD44 int/low FoxP3 - CD62L + T cells (Tnaive) or CD4 + CD44 Hi FoxP3 - type 1 regulatory (Tr1) T cell subsets from 10BiT murine splenocytes, activated them, and transferred them into wounds. In vitro , dermal fibroblasts were cocultured with Tnaive or Tr1 and the effect on extracellular matrix (ECM) regulation was analyzed. Results: The anti-inflammatory and antifibrotic effects of CD4 + cells on SCID wounds were lost with cells from IL-10 -/- mice. Adoptive transfer of Tr1 into SCID mice resulted in accelerated wound closure at d7 with reduced fibrosis at d28, with Tr1 favoring hyaluronan production by fibroblasts, an ECM molecule implicated in IL-10-induced regenerative healing. Conclusions: IL-10 producing T-lymphocytes, specifically Tr1, regulate inflammatory cell cytokine expression to promote HA-rich ECM deposition and attenuate fibrosis. Promoting IL-10 producing lymphocytes in wounds may be a therapeutic target to promote regenerative wound healing.

The therapeutic and commercial landscape of stem cell vesicles in regenerative dermatology

“…Similar observations have also been recorded for bone marrow MSC-EVs (BMSC-EVs), which were observed to inhibit T lymphocyte proliferation, boost regulatory T cell numbers, and increase the secretion of anti-inflammatory cytokines such as TGF-β1 and IL-10 [35]. These observations have clear implications in dermal wound healing, since the potent antifibrotic and proregenerative effects of IL-10 have been well described [36,37]. However, wound healing models in which there is an abolition of T cells (athymic mouse models and antibody-mediated depletion) have frequently provided variable results, with examples of regulatory CD4 + and cytotoxic CD8 + T cell neutralisation or knockout generating unreproducible and often contradictory effects on parameters such as collagen deposition or wound breaking strength [38,39].…”

Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy

“…Bollyky et al ( 130 ) demonstrated that HMW-HA promoted the induction of Tr1 cells from effector memory T-cell precursors via binding its receptor, CD44, in humans and mice. The produced IL-10 from Tr1 cells also enforces HMW-HA production from fibroblast via activating the STAT3-dependent signaling pathway in mice ( 131 , 132 ). Therefore, the crosstalk of Tr1 cells and extracellular matrix such as HMW-HA could be essential for wound healing in inflamed tissues.…”

Advances in Immunomodulatory Mechanisms of Mesenchymal Stem Cells-Derived Exosome on Immune Cells in Scar Formation

“…For example, IL-10producing CD4+ T lymphocyte subsets, specifically Th1, regulate inflammatory cell cytokine expression to selectively attenuate dermal wound fibrosis. 149 While the NKG2A/CD94 complex (an inhibitory marker of the T cells) was specifically upregulated, it was demonstrated that the downregulation of cytotoxic CD8+ T cells is a keloid signature in peripheral blood and keloid lesions. 150 This may explain the significant decrease in CTLs within the scar tissue boundary.…”