Keratinocyte-derived TGFβ is not required to maintain skin immune homeostasis

Abstract

Background: Transforming growth factor beta 1 (TGFβ) is known to be a regulator of autoimmunity. Loss of TGFβ leads to severe multi-organ autoimmunity in mice. In skin, role of TGFβ in suppressing autoimmunity is unclear. Objective: Determine whether Keratinocyte (KC)-derived TGFβ is required for skin immune homeostasis. Methods: We generated K14-CreER T2 TGFβ1 fl/fl (TGFβ DKC) mice allowing for tamoxifen-induced deletion of TGFβ1 in KC. The phenotype of skin was analyzed and compared to mice in which epidermal activation of TGFβ is impaired. Results: KC was the major source of TGFβ in epidermis. Topical tamoxifen application led to efficient TGFβ1 deletion. The expected acanthosis was observed but no inflammatory infiltrate or altered numbers of resident immune cells were evident. Similarly, Itgb6 À/À x K14Cre Itgb8 f/f (Itgb6 À/À Itgb8 DKC) mice lacking both epidermal TGFβ-activating integrins showed no evidence of cutaneous inflammation. Conclusions: KC-derived TGFβ and epidermal TGFβ activation are not required to suppress skin autoimmunity in steady state.

Transcriptomic Profiling Revealed Plexin A2 Downregulation With Migration and Invasion Alteration in Dacarbazine-Treated Primary Melanoma Cells

“…All three molecules have been previously shown to be implicated in tumor progression and metastasis of various cancer types including melanoma ( 22 – 24 , 29 , 30 ). ITGB8 is involved in TGF-β activation ( 31 , 32 ), which was found to be downregulated after DTIC treatment in the present study. MMP1 is an important enzyme that is activated by TGF-β and mediates extracellular matrix degradation, especially those of collagen type I, II and III ( 33 , 34 ).…”

Competition for Active TGFβ Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche

“…Potential epidermal sources of TGFb to support Trm cell persistence include KCs, Langerhans cells (LCs), dendritic epidermal T cells (DETCs), and Trm cells (Yang et al, 2019). Trm cells are unaffected by the absence of LCs and DETCs, indicating that these cell types are not obligate sources of TGFb (Mohammed et al, 2016;Zaid et al, 2014).…”

“…Trm cells are unaffected by the absence of LCs and DETCs, indicating that these cell types are not obligate sources of TGFb (Mohammed et al, 2016;Zaid et al, 2014). Since KCs are the largest source of TGFb in the epidermis (Yang et al, 2019), we hypothesized that KC-derived TGFb is required to support Trm cell persistence. To test this, we used Krt14-creER T2 x Tgfb1 fl/fl mice (Tgfb DKC ) that allow for the inducible ablation of Tgfb1 from KCs.…”

TGF-β: Many Paths to CD103+ CD8 T Cell Residency

“…While resident DC expressing α v integrins in the epidermis do not seem to play a role in the development of epidermal CD103 + CD8 T RM cells, keratinocytes expressing α v β 6 and α v β 8 are required for the development and maintenance of CD103 + CD8 T RM cells in the epidermis [ 63 , 64 , 65 ]. Several cell types in the epidermis, including Langerhans cells, keratinocytes, dendritic epidermal T cells (DETC), and CD8 T RM cells, can express TGF-β and provide a source to support CD103 + CD8 T RM cell residence [ 66 ]. Nevertheless, continued exposure to TGF-β derived from CD8 T RM cells, but not Langerhans cells, keratinocytes, or DETC, is required for the long-term persistence of epidermal CD103 + CD8 T RM cells [ 64 , 67 , 68 ].…”