Journal
EXPERIMENTAL DERMATOLOGY
Volume 19, Issue 8, Pages 723-729Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-0625.2010.01092.x
Keywords
IL-1; IL-1Ra; skin; skin grafts; T cells
Categories
Funding
- National Health and Medical Research Council [351439]
- Cancer Council Australia
- Cancer Research Institute (New York)
- AUSAID
- Lions Medical Research Fellowship
- Queensland Government
- Arthritis Queensland
- ARC
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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-1 beta 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-1 beta 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-1 beta-associated skin graft rejection and induction of antigen-specific CD8 T-cell responses. Enhancing IL-1 beta signalling, via blocking of the IL-1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7-associated cancers.
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