Hair Follicle Mesenchyme-Associated PD-L1 Regulates T-Cell Activation Induced Apoptosis: A Potential Mechanism of Immune Privilege

Abstract

The immune privilege (IP) of hair follicles (HFs) has been well established in previous studies. However, whether cultured HF cells still exhibit IP properties, the individual factors involved in this process, and the detailed mechanisms that drive and maintain IP, are largely unidentified. We found preferential expression of IP-associated genes in cultured HF dermal papilla and dermal sheath cup cells (DSCCs) compared with non-follicular fibroblasts (FBs) at passage 4, suggesting a potential for functional IP. Notably, programmed cell death 1 ligand 1 (PD-L1) was significantly upregulated in DSCCs and dermal papilla cells relative to FBs. IFNγ secretion from peripheral blood mononuclear cells (PBMCs) co-cultured with histoincompatible DSCCs was significantly lower than with FB and higher percentages of early apoptotic, Annexin V+ cells were observed in PBMC co-cultured with DSCCs. Knockdown of PD-L1 translation by silencing interfering RNA in DSCCs enabled increased IFNγ secretion by PBMCs, whereas transfection of pCMV6-XL4/hPD-L1 in FB significantly reduced IFNγ secretion and increased apoptosis in co-cultured PBMCs. We also found that apoptosis in allogeneic T cells induced by DSCCs was largely dependent on the mitochondrial pathway. Our study suggests IP properties are exhibited in cultured DSCCs in part through expression of negative co-signaling molecule PD-L1.

Alopecia areata: a review of disease pathogenesis

“…Firstly, the absence of lymphatic drainage and presence of the extracellular matrix may serve as physical barriers to invading immune cells . Any immune cells capable of breaching the physical barriers are then presumably targeted by proapoptotic Fas ligand and programmed cell death 1 ligand 1 (PD‐L1) . Although several studies have failed to demonstrate FasL on major histocompatibility complex (MHC)‐I‐negative HFs, PD‐L1 is found on dermal sheath cup cells and dermal papilla cells …”

“…[24][25][26] Any immune cells capable of breaching the physical barriers are then presumably targeted by proapoptotic Fas ligand and programmed cell death 1 ligand 1 (PD-L1). [27][28][29][30] Although several studies have failed to demonstrate FasL on major histocompatibility complex (MHC)-I-negative HFs, PD-L1 is found on dermal sheath cup cells and dermal papilla cells. 27,28,31 HF cells also produce factors that suppress MHC expression to protect their sequestered antigens.…”

“…[27][28][29][30] Although several studies have failed to demonstrate FasL on major histocompatibility complex (MHC)-I-negative HFs, PD-L1 is found on dermal sheath cup cells and dermal papilla cells. 27,28,31 HF cells also produce factors that suppress MHC expression to protect their sequestered antigens. These IP guardians include [24][25][26] transforming growth factor (TGF)-b, a-melanocyte-stimulating hormone (MSH), indoleamine-2,3-dioxygenase (IDO), protein red encoded by the IK gene (red/IK), interleukin (IL)-10, calcitonin gene-related peptide, insulinlike growth factor-1 and somatostatin.…”

Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors

“…The underlying pathophysiology of AA is unclear, but a CD4 + ‐and CD8 + ‐mediated process against the hair follicle and the presence of specific IgG autoantibodies in the peripheral blood corroborate the hypothesis of an autoimmune aetiology. Additionally, as the hair follicle dermal‐sheath cup cell expresses PD‐L1, PD‐1 inhibitors may directly induce AA . A severe combined immunodeficiency mouse model revealed that melanocyte antigens Gp100‐derived G9‐209, G9‐280 and MART‐1 (27‐35) have been shown to function as the target antigens in experimental AA, raising the possibility of melanocyte‐specific cytotoxic T cells in patients with melanoma .…”

Immune checkpoint inhibitor-associated alopecia areata

“…On the other hand, their number appeared to be reduced in lesional AA skin compared with healthy skin . PD‐L1 is also expressed on dermal papilla and dermal sheath cup cells . Immune checkpoint inhibitors might induce the collapse of HF‐IP by the reduction of immunosuppressive signals mediated via PD‐1/PD‐L1, resulting in the recognition of hair follicle autoantigens by NKG2D + CD8 + T cells in patients with malignant melanoma (Fig.…”