IL-1 signalling determines the fate of skin grafts expressing non-self protein in keratinocytes.
Although IL-1 is a known inflammatory cytokine during pathogen infection, the role of IL-1 in skin graft rejection, particularly where foreign antigen is expressed exclusively in keratinocytes, is less understood. Here, we use a syngeneic skin graft system, where antigens are expressed in epithelial cells via either a keratin 14 or keratin 5 promoter, to explore the role of IL-1 in graft rejection and induction of epithelial antigen-specific effector CD8(+) T-cell function. Keratin 5 ovalbumin (K5mOVA) transgenic skin grafts destined for rejection demonstrated increased expression of IL-1beta and its receptors compared to K14 HPV16 E7 transgenic grafts that do not reject spontaneously. Rejection of OVA grafts lacking the IL-1 receptor (IL-1R1) was delayed and associated with decreased numbers of antigen-specific CD8 T cells. In contrast, K14E7 grafts survived on immunocompetent, syngeneic recipients with decreased graft levels of IL-1beta and IL-1R1 and 2. However, in the absence of the IL-1 receptor antagonist, IL-1Ra, skin grafts were spontaneously rejected and an E7-specific CD8 T-cell response was primed. Thus, expression of the HPV16E7 oncoprotein in epithelial cells prevents IL-1beta-associated skin graft rejection and induction of antigen-specific CD8 T-cell responses. Enhancing IL-1beta signalling, via blocking of the IL-1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7-associated cancers.
Hadis
Usriansyah
U
The University of Queensland Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Woolloongabba, Qld, Australia.
Leggatt
Graham R
GR
Thomas
Ranjeny
R
Frazer
Ian H
IH
Kovacs
Eva M
EM
D000818:Animals; D006084:Graft Rejection / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D053547:Keratin-14 / Q000378:metabolism; D053555:Keratin-5 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D010047:Ovalbumin / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016038:Skin Transplantation / Q000502:physiology*
D007375:Interleukin-1; D053547:Keratin-14; D053555:Keratin-5; D050725:Papillomavirus E7 Proteins; D017472:Receptors, Interleukin-1; C059731:oncogene protein E7, Human papillomavirus type 16; D010047:Ovalbumin