Objective: While tissue injury and repair are known to involve adaptive immunity, the profile of lymphocytes involved and their contribution to dermal scarring remain unclear. We hypothesized that restoration of T cell deficiency attenuates dermal scarring. Approach: We assessed the temporal-spatial distribution of T lymphocytes and their subtypes during the physiological dermal wound repair process in mice. Also, we compared the scarring outcomes between wild-type (WT) and severe combined immunodeficient (SCID) mice, which are lymphocyte deficient. Complementary gain-of-function experiments were performed by adoptively transferring lymphocyte subsets to validate their contribution to tissue repair in wounded SCID mice. Results: CD4+ T lymphocytes were present within dermal wounds of WT mice beginning on day 1 and remained through day 30. Wounds of SCID mice exhibited accelerated closure, increased inflammation, limited neovascularization, and exacerbated scarring compared with WT mice. Conversely, transfer of either mixed B and T lymphocytes or CD4+ lymphocytes alone into SCID mice resulted in moderated healing with less inflammation, collagen deposition, and scarring than control SCID wounds. In contrast, transfer of other lymphocyte subsets, including helper T lymphocytes (CD3+CD4+CD25-), CD8+ T cells and B cells, or regulatory T lymphocytes (CD4+CD25+CD127low), did not reduce scar. Innovation: The finding that lymphocytes delay wound healing but reduce scar is novel and provides new insights into how dermal scarring is regulated. Conclusion: Our data support a suppressive role for CD4+ T cells against inflammation and collagen deposition, with protective effects in early-stage dermal wound healing. These data implicate adaptive immunity in the regulation of scarring phenotypes.
Keywords: adaptive immunity; extracellular matrix; inflammation; lymphocytes; wound healing.
© Xinyi Wang et al., 2019; Published by Mary Ann Liebert, Inc.
Conflict of interest statement
The article was written by the authors and ghostwriting services were not used. Editorial support provided by Drs. Hector Martinez-Valdez and Monica Fahrenholtz at the Office of Surgical Research Administration at TCH.
Scar-free healing: from embryonic mechanisms to adult therapeutic intervention.Philos Trans R Soc Lond B Biol Sci. 2004 May 29;359(1445):839-50. doi: 10.1098/rstb.2004.1475. Philos Trans R Soc Lond B Biol Sci. 2004. PMID: 15293811 Free PMC article. Review.
Absence of CD4 or CD8 lymphocytes changes infiltration of inflammatory cells and profiles of cytokine expression in skin wounds, but does not impair healing.Exp Dermatol. 2014 Mar;23(3):189-94. doi: 10.1111/exd.12346. Exp Dermatol. 2014. PMID: 24521099 Free PMC article.
Dermal microvascular injury in the human peripheral blood lymphocyte reconstituted-severe combined immunodeficient (HuPBL-SCID) mouse/skin allograft model is T cell mediated and inhibited by a combination of cyclosporine and rapamycin.Am J Pathol. 1998 Aug;153(2):627-38. doi: 10.1016/S0002-9440(10)65604-0. Am J Pathol. 1998. PMID: 9708821 Free PMC article.
Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors.Diabetes. 1993 Jan;42(1):44-55. doi: 10.2337/diab.42.1.44. Diabetes. 1993. PMID: 8093606
CD44-dependent inflammation, fibrogenesis, and collagenolysis regulates extracellular matrix remodeling and tensile strength during cutaneous wound healing.Matrix Biol. 2019 Jan;75-76:314-330. doi: 10.1016/j.matbio.2018.06.004. Epub 2018 Jun 9. Matrix Biol. 2019. PMID: 29894820 Free PMC article. Review.
- Zhang C, Li L, Feng K, Fan D, Xue W, Lu J. “Repair” Treg cells in tissue injury. Cell Physiol Biochem 2017;43:2155–2169 - PubMed
- Chazaud B. Macrophages: supportive cells for tissue repair and regeneration. Immunobiology 2014;219:172–178 - PubMed
- Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008;453:314–321 - PubMed
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