Keratinocytes Function as Accessory Cells for Presentation of Endogenous Antigen Expressed in the Epidermis

Abstract

The precise contribution(s) of skin dendritic cells (DCs) to immune responses in the skin has not been well delineated. We developed an intradermal (i.d.) injection model in which CD8+ T (OT-I) cells that express ovalbumin (OVA)-peptide-specific T-cell receptors (Vα2/Vβ5) are delivered directly to the dermis of transgenic (Tg) mice expressing OVA in the epidermis. Following i.d. injection, these mice reliably develop skin GvHD by day 7. To determine the relative contribution of LCs to the ensuing graft-versus-host (GvHD) - like reaction, we generated K14-OVA × Langerin-Diphtheria-Toxin-Receptor (Langerin-DTR) Tg mice to allow conditional ablation of LCs in the epidermis. To delineate the role of dermal dendritic cells (dDCs) in the reaction we also generated K14-OVA Tg chimeras using beta-2-microglobulin-deficient (b2m) congenic donor bone marrow cells. Dermal DCs in these mice cannot present OVA to OT-I cells while the LC are antigen presentation competent. Unexpectedly, OT-I cell injection into diphtheria toxin (DT)-treated b2m→K14−OVA × Langerin-DTR Tg mice resulted in skin GvHD. Thus, in vivo, both LC and dDC appear to be dispensable for induction of keratinocyte-directed, CD8-mediated effector immune responses. Furthermore and surprisingly, OVA-expressing epidermal cells depleted of LCs that could not initiate allogeneic epidermal lymphocyte reactions, activated naïve OT-I cells in vitro. These results indicate that keratinocytes may function as accessory cells-competent to prime naïve skin-reactive T cells.

Self-Antigen Presentation by Keratinocytes in the Inflamed Adult Skin Modulates T-Cell Auto-Reactivity

“…In a similar study, mice expressing a model antigen in keratinocytes developed a graft versus host like reaction after intradermal injection of CD8 + T cells carrying the respective specificity (Kim et al, 2009). In this case, antigen presentation by Langerhans cells and dendritic cells was experimentally excluded.…”

“…In this case, antigen presentation by Langerhans cells and dendritic cells was experimentally excluded. Thus, it was proposed that keratinocytes can directly prime naïve CD8 + T cells in the adult skin (Kim et al, 2009).…”

Antigen-Specific CD8 T Cells Can Eliminate Antigen-Bearing Keratinocytes with Clonogenic Potential via an IFN-γ-Dependent Mechanism

“…Minor alloantigens present on grafted epithelium, provided they are directly presented on bone marrowderived cells, can invoke strong immune responses, and are also rejected by CD8-dependent mechanisms (Oukka et al, 1997). KCs are capable of processing and presenting antigen directly (Kim et al, 2009), although transgenic antigens expressed in KCs can also be cross-presented by local CD103 þ antigen-presenting cells (Bedoui et al, 2009). The precise effector mechanisms leading to skin graft rejection by MHC class I-or II-restricted T cells are undefined (Horner et al, 2008).…”

Clinical perspectives and murine models of lichenoid tissue reaction/interface dermatitis

“…Keratinocytes of K14-mOVA mice presented OVA on their MHC class I, and stimulated the proliferation of OT-I cells with OVA-specific TCRs independently of LCs [14,15]. K5-or K14-mOVA Tg mice developed LTR/IFD reactions after adoptive transfer of CD8 + OT-I cells (Fig.…”