Tropism of herpes simplex virus type 1 to nonmelanoma skin cancers

Background Current treatments for nonmelanoma skin cancer include surgery, Mohs micrographic surgery, radiation, cryosurgery, photodynamic therapy, local chemotherapy and application of immunomodulators such as imiquimod. However, all have a 5‐year recurrence rate of 1–40%. Gene therapy for the treatment of skin cancers is a promising new approach, as delivery of the vectors to the skin is simple and safety issues can be properly addressed. Objectives To develop an ex‐vivo organ culture system for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) tumours, and to test the feasibility of applying oncolytic viruses to these tumours. Methods We first optimized conditions for the maintenance of BCC and SCC tissues in organ culture, and demonstrated viability of the tissues ex vivo for 3–7 days. The tropism of two potential oncolytic viral vectors, herpes simplex virus type 1 (HSV‐1) and adenovirus (AD), was next evaluated. Results Immunohistological analysis revealed that HSV‐1 targeted tumour cells that expressed p63 and did not express keratin 15 or keratin 14 markers of keratinocytes. Further examination indicated that uninfected BCC and SCC tissues express two isoforms of p63 mRNA, and HSV‐1 infection specifically enhanced expression of the TAp63 isoform. Furthermore, following infection, both HSV‐1 and AD induced apoptosis in the BCC and SCC cells as indicated by the induction of activated caspase‐3. Conclusions The results indicated a specific pattern of viral tropism to skin cancer cells that are critical for maintenance of the tumour. This new experimental system should aid in the analysis of new therapeutic modalities, such as oncolytic viruses, for future treatment of these skin tumours.     

The role of polymorphonuclear leukocyte infiltration in herpes simplex virus infection of murine skin

Abstract We undertook the present study to investigate the role of polymorphonuclear leukocytes (PMN) in defending skin against herpes simplex virus (HSV) infection. For this purpose, we established a mouse model of cutaneous HSV infection. The hind limb footpad skin of 4-week-old ICR mice was abraded linearly once with a feather edge file and infected with various strains of HSV with different virulence. In uninfected control mice, PMN appeared at the abraded skin lesion within 24 h, and were eliminated from the epidermis after 3 days. Mice inducted with a highly virulent strain of HSV demonstrated wide and severe erythematous lesions of the footpad skin and histologically, virus antigen-positive ballooning degenerated keratinocytes were observed. However, in infections with attenuated strains of HSV, the epidermis was regenerated and a viral antigen was discharged within 5 days, together with any infiltrated PMN. Macrophages and NK cells numbered less than PMN. In mice treated with anti-PMN antiserum before HSV infection, PMN infiltration was significantly suppressed 1 day after infection, and these animals developed a severe cutaneous disease even if infected with an attenuated virus. These results indicate the importance of PMN in the control of HSV cutaneous infections, especially in the primary infectious phase. Received: 17 April 1998 / Received after revision: 3 September 1998 / Accepted: 11 September 1998     

Extramammary Paget's disease with superimposed herpes simplex virus infection: immunohistochemical comparison with cases of the two respective diseases

We describe an extremely rare case of genital Paget's disease with superimposed herpes simplex virus (HSV) infection. We also describe immunohistochemical comparison of this lesion with 19 cases of genital Paget's disease and 12 cases of skin lesions caused by HSV or varicella-zoster virus. The Paget cells expressed simple epithelial keratins (CK7 and CK19) and carcinoembryonic antigen (CEA), but did not express stratified epithelial keratins (CK1, CK2e, CK10, CK5/8, CK14). Conversely, the virus-infected keratinocytes were positive for stratified epithelial keratins but negative for simple epithelial keratins and CEA. In the present case, simple epithelial keratins, stratified epithelial keratins, CEA and HSV were heterogeneously expressed in the ballooning and multinucleated giant cells. These results suggest that these cells were derived from keratinocytes and Paget cells and that the production of many multinucleated giant cells resulted from the virus-mediated cell fusion between Paget cells and neighbouring keratinocytes.     

Virus replication and induction of interferon in human epidermal keratinocytes following infection with herpes simplex virus

Keratinocyte cultures derived from surgical skin specimens of healthy newborns and adults were infected with herpes simplex virus (HSV) type 1 or 2. Typical HSV cytopathic effects involved all cell layers in stratified colonies, and paralleled the production of infectious virus. Virus growth curves and production of virus were comparable in newborn and adult keratinocytes. Interferon (IF) production by keratinocytes paralleled the yield of virus over at least 72 h, and was greater in cultures of adult cells than cultures from newborns. UV irradiation of HSV resulted in progressive virus inactivation and a parallel reduction in induced IF. This suggests that IF production was related to virus replication, and that irradiated (noninfectious) HSV DNA did not contribute significantly to the generation of IF in this system. These results establish that human epidermal keratinocytes can serve as a model system for quantitative assessment of herpes simplex virus infection.     

Detection of multinucleated giant cells in differentiated keratinocytes with herpes simplex virus and varicella zoster virus infections by modified Tzanck smear method

Herpes simplex virus (HSV) and varicella zoster virus (VZV) infections induce the formation of intraepidermal vesicles containing acantholytic cells and multinucleated giant cells in the skin. The Tzanck smear is most commonly used to diagnose cutaneous herpetic infections, but it leads to many false‐positive and ‐negative results. This study aimed at establishing a method detecting much larger multinucleated giant cells using the Tzanck smear because these cells characterize the viral cytopathic effect in skin infections. Morphological changes were analyzed among several layers of keratinocytes with HSV‐ or VZV‐related cutaneous lesions, clinically and in vitro. We compared the sensitivity of the Tzanck smear to detect large acantholytic cells using both the removed roof tissue part (our approach) and the floor of the lesion (conventional approach) of a fresh vesicle. Large acantholytic cells were detected 2.0‐times more frequently in the removed roof tissue part of the vesicle than in the floor of the lesion. Round cells were much larger in the removed roof tissue part of the vesicle corresponding to the granular or prickle layer of the epidermis than in its floor of the lesion corresponding to the basal or prickle layer with the Tzanck smear. Differentiated cultured keratinocytes formed multinucleated giant cells by cell‐to‐cell fusion with resolution of cell membrane with VZV infection. Differentiated keratinocytes promote multinucleated giant cell formation by cell‐to‐cell fusion with HSV‐1 or VZV infection. To increase the sensitivity, the Tzanck smear should be prepared from the removed roof tissue part of a fresh vesicle to detect multinucleated giant cells in herpetic infections.     

Epidermal Langerhans cells,dermal dendritic cells,and keratinocytes in viral lesions of skin and mucous membranes: an immunohistochemical study

Summary We wanted to evaluate the eventual expression of viral antigens and MHC class II products by keratinocytes as well as the alterations of epidermal Langerhans cells and dermal dendritic cells in viral lesions of skin and mucous membranes. Therefore we investigated 68 biopsy specimens of protracted viral lesions, such as warts, condylomas, and mollusca contagiosa, and of rapidly resolving viral lesions such as herpes simplex virus infection. For this we used immunohistochemical staining techniques and several monoclonal and polyclonal antisera. In most cases investigated viral antigens (human papilloma virus antigens or herpes simplex virus type 1 antigens) could be demonstrated in keratinocytic nuclei. Except for a few viral lesions in which epidermal Langerhans cells were rather numerous, epidermal Langerhans cells were reduced in number or absent in almost all viral lesions. Moreover, epidermal Langerhans cells and dermal dendritic cells showed changes in morphology, distribution, and immunophenotype. These alterations may be caused by a toxic effect of the virus on dendritic cells. HLA-DR⁺ keratinocytes could be identified in few viral lesions onlyl HLA-DQ⁺ keratinocytes were not seen. Possible explanations for this lack of MHC class II expression by keratinocytes are discussed.Aspirant of the NFWO (National Fund for Scientific Research)     

Epidermal Langerhans cells efficiently mediate CD1a-dependent presentation of microbial lipid antigens to T cells

Langerhans cells are a critical component of skin immunity, capable of capturing protein antigens in the epidermis and presenting them to specific T cells in the context of major histocompatibility complex class II molecules. Recently, a major histocompatibility complex independent pathway of lipid antigen presentation has been identified and is mediated by molecules of the CD1 family (CD1a, CD1b, CD1c, and CD1d). Because Langerhans cells are professional antigen-presenting cells and express CD1a molecules prominently, we hypothesized that Langerhans cells might play a role in T cell responses directed against not only peptide antigens but also lipid antigens. Here, we show that freshly isolated immature Langerhans cells as well as mature Langerhans cells that have migrated from the epidermis are efficient in presenting foreign microbial lipid antigens to specific T cells whereas dermal dendritic cells express much less CD1a molecules and function inefficiently. Further, we found that Langerhans cells migrating from epidermal sheets that were exposed to microbial lipid antigens expressed lipid-antigen-loaded CD1a molecules on the cell surface, resulting in activation of specific T cells. These results underscore an outstanding ability of Langerhans cells to mediate CD1a-dependent lipid antigen presentation. Thus, Langerhans-cell-mediated skin immunity may involve T cell recognition of both peptide and lipid antigens.     

Use of the fluorescence-activated cell sorter to quantitate and enrich for subpopulations of human skin cells

A variety of immunologic staining techniques were compared in a quantitative study of antigen expression by human epidermal cells. Virtually all nucleated epidermal cells express beta 2-microglobulin, which is associated with HLA-A, -B, and -C antigens, whereas only about 4% expressed T6, an antigen expressed by Langerhans cells but not other cells in the skin. With the fluorescence-activated cell sorter (FACS), epidermal cell suspensions were selectively enriched 10- to 15-fold for T6-positive Langerhans cells. An average of 6.5% of cells were specifically stained by anti-HLA-DR antibody. When dispersed cells stained with anti-DR plus peroxidase were examined with the technique of immunoelectron microscopy, only mononuclear leukocytes (probably Langerhans cells) were stained. After separating HLA-DR positive skin cells with the FACS, the DR-positive population but not the DR-negative population stimulated proliferation of allogeneic responder lymphocytes, indicating that sorted cells are metabolically active. We conclude that HLA-DR antigen is not expressed by keratinocytes in normal human skin cell suspensions and that the FACS can be used to selectively enrich or deplete skin cell suspensions of antigenically distinct subpopulations such as Langerhans cells.     

Immune evasion during varicella zoster virus infection of keratinocytes

T cells are sensitized during varicella‐zoster virus (VZV) infection and are important for control of viral spread and reactivation. In this report, we show that human keratinocytes infected with VZV inhibited upregulation of major histocompatibility complex (MHC) class I, MHC class II and intercellular adhesion molecule‐1 after interferon (IFN)‐γ treatment. The ability of keratinocytes to upregulate MHC class I in response to IFN‐α, tumour necrosis factor (TNF)‐α and Toll‐like receptor (TLR)‐3 ligand was also diminished upon VZV infection. VZV‐infected keratinocytes treated with IFN‐γ had significantly reduced capacity to stimulate antigen‐specific T cells compared with uninfected cells. Interference with IFN‐α, TNF‐α, IFN‐γ and TLR‐3 signalling in keratinocytes by VZV may contribute to immune evasion of the adaptive immune response.     

Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component

Erythema multiforme (EM) is a clinical conundrum the name of which reflects the broad morphological spectrum of the lesions. Molecular and immunologic evidence that herpes simplex virus (HSV) causes a subset of EM lesions [herpes-associated EM (HAEM)] is reviewed, and new data are presented which suggest that autoreactive T-cells triggered by virus infection play an important role in HAEM pathogenesis. Disease development begins with viral DNA fragmentation and the transport of the DNA fragments to distant skin sites by peripheral blood mononuclear cells (PBMCs). HSV genes within DNA fragments deposited on the skin [notably DNA polymerase (Pol)] are expressed, leading to recruitment of HSV-specific CD4+ Th1 cells that respond to viral antigens with production of interferon-gamma (IFN-gamma). This step initiates an inflammatory cascade that includes expression of IFN-gamma induced genes, increased sequestration of circulating leukocytes, monocytes and natural killer (NK) cells, and the recruitment of autoreactive T-cells generated by molecular mimicry or the release of cellular antigens from lysed cells. The PBMCs that pick up the HSV DNA [viz. macrophages or CD34+ Langerhans cells (LC) precursors], their ability to process it, the viral proteins expressed in the skin and the presence of epitopes shared with cellular proteins may determine whether a specific HSV episode is followed by HAEM development. Drug-associated EM (DIEM) is a mechanistically distinct EM subset that involves expression of tumor necrosis factor alpha (TNF-alpha) in lesional skin. It is our thesis that the polymerase chain reaction (PCR) assay for HSV DNA detection in lesional skin and staining with antibodies to IFN-gamma and TNF-alpha, are important criteria for the diagnosis of skin eruptions and improved patient management.     

Topische Immunmodulation in der Dermatologie

Summary: Immunomodulators include both immunostimulatory and immunosuppressive agents.
If successful, topical immunotherapy may represent an important improvement in the therapy of inflammatory dermatoses, viral infections and cancers of the skin and genital mucosa. This rather old concept
has emerged some 100 years ago, but only recently have its basic mechanisms been elucidated. Topical immunotherapy using obligate contact sensitizers such
as diphencyprone or dinitrochlorobenzene elicit hapten‐mediated immune responses, which involve specific antigens or act merely by the induction of an inflammatory infiltrate. They have been used against viral (e. g. common warts) and autoimmune diseases (e. g. alopecia areata). Newer agents such as imidazoquinolines (imiquimod and resiquimod) act by cytokine secretion from monocytes/macrophages (interferon‐α, interleukin‐12, tumour‐necrosis factor‐α). The locally generated immune milieu leads to a
Th₁‐dominance and cell‐mediated immunity that have been clinically used to treat viral infections such as HPV, HSV and mollusca and cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. While these agents improve antigen‐presentation by dendritic cells, they also act on B‐cells leading to the synthesis of antibodies such as IgG_2a much
like the recently discovered immunostimulatory CpG sequences that stimulate innate immunity. These sequences act as ?danger signals” as they occur in bacterial and viral DNA but are selectively methylated and inactivated in the mammalian genome. They share the induction of the same cytokines like imidazoquinolines, while they display different magnitudes and kinetics of the response. On the other hand, the topical immunosuppressive tacrolimus has been used with great success in the treatment of chronic inflammatory diseases such as atopic dermatitis in children and adults. Topical immunotherapy with both immunostimulatory and immunosuppressive agents bears potential for effective and patient‐friendly treatment of inflammatory, infectious and cancerous skin diseases. Due to their adjuvant properties immunoenhancers may also improve conventional (protein) and DNA vaccination against cancer, atopy and allergies.     

Role of Langerhans cells in cutaneous protective immunity: is the reappraisal necessary?

Langerhans cells (LC) are constantly exposed to external antigens and pathogens, and they are the cutaneous counterpart of dendritic cells (DC). DC not only act as professional antigen presenting cells to induce antigen-specific T cells for adaptive immune responses, but they also initiate a cascade of innate immune responses by sensing these danger signals. However, recent studies challenge the classical paradigm to position LC in the center of cutaneous immunity. Although LC express toll-like receptors (TLRs) that recognize bacterial and viral products, exposure to pathogen-associated TLR ligands triggers neither sufficient LC maturation nor good production of cytokines and chemokines. LC also lack the ability to produce IFN-gamma by any stimuli, and together with the characteristics of LC that are prone to produce Th2-type chemokines and to produce much less IL-12 in the presence of keratinocyte-derived GM-CSF, LC primarily may not have the character to induce Th1- and Tc1-type immune responses necessary for protective cellular immunity. Moreover, LC maturation is inhibited, rather than enhanced, by type I IFNs that are abundantly produced in viral infections in the skin microenvironment. Finally, recent data suggest that LC may not directly present viral antigens to T cells for their activation in mouse models of cutaneous viral infection. The alternative player in protective immune responses may be surrounding keratinocytes, which may modulate LC functions indirectly. Dermal DC may also participate in this scheme. Further studies are required to clarify the role of LC in their interplay with keratinocytes and other DC subsets, and to draw the entire picture of the cutaneous immune system against pathogens.     

Antigen presentation in patients with recrudescent orofacial herpes simplex virus infections

Recovery from epidermal herpes simplex virus (HSV) infection depends primarily on development of an effective cell-mediated immune response, possibly generated following antigen (Ag) presentation by epidermal cells (EC). The ability of EC to present HSV Ag was investigated in 12 subjects with occasional recrudescent facial HSV infections. All had circulating HSV specific antibodies and cell-mediated immunity to the virus. Peripheral blood mononuclear cell suspensions, depleted of antigen presenting cells (APC) by glass adherence and then enriched for T cells by adsorption on nylon wool columns, did not proliferate in response to HSV Ag. Both EC suspensions, prepared from suction blister roofs, and glass-adherent peripheral blood mononuclear cells (AC) preincubated with ultraviolet-inactivated HSV, reconstituted the T-cell proliferative response to HSV. EC were more efficient than AC at presenting HSV Ag to T cells. Depletion of CD1+ cells from EC suspensions by cell sorting reduced their ability to present HSV Ag and augmentation of CD1+ cell numbers supplemented it. Preincubation of EC or AC with monoclonal antibodies to major histocompatibility complex class II antigens DP, DQ or DR, blocked the lymphoproliferative response to HSV Ag. Evidence was obtained that cells co-ordinately expressing products of the DP, DQ and DR loci are involved in presentation of HSV Ag by both EC and AC.     

SSA/Ro antigen expression in simian virus 40-transformed human keratinocytes

SSA/Ro antigen is a soluble cellular component to which antibodies are frequently produced in patients with Sj?gren's syndrome and systemic lupus erythematosus. Its exact location within the cell has yet to be determined. In this study we report the expression of SSA/Ro antigen in simian virus 40 (SV40)-transformed keratinocytes. The locations of SSA/Ro, U1RNP, and DNA antigens were studied by indirect immunofluorescence using monospecific antibodies. SSA/Ro antigen was detected in both the nucleus and cytoplasm of SV40-transformed keratinocytes tested with three monospecific sera. Primary cultured keratinocytes derived from adult human skin showed localized immunofluorescent staining within the nucleus. When Ca++ concentration of the medium was switched to 0.05 mM, these cells expressed cytoplasmic SSA/Ro antigens within 48 h. Depletion of the antibody activity with insolubilized human spleen extract abolished the staining. Surface expression of this antigen could not be detected in either primary or transformed cells. Localization of U1RNP and DNA was not altered. These results indicate that expression of SSA/Ro antigen in human keratinocytes is modulated by SV40 infection and that this antigen is expressed to a greater degree in cells that are less differentiated, transformed, or proliferating.     

Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161.

BACKGROUND: The genetic and immunological basis for psoriasis is unknown. Through the use of a severe combined immunodeficient mouse-human skin model, T cells have been shown to induce psoriasis, which points to a pathological role for such immunocompetent cells. During ongoing studies using this model, a previously overlooked subset of immunocytes expressing receptors typically present on natural killer (NK) cells was discovered, which may shed new light on the genetic susceptibility for psoriasis. OBSERVATIONS: Immunocytes from a psoriatic patient were injected into engrafted allogeneic normal human skin and produced a psoriatic plaque. Moreover, the disturbed epidermal environment spread to induce a greater than 20-fold increase in thickness of adjacent mouse epidermis with prominent elongation of rete pegs. Thus, rather than observing the predicted graft-vs-host reaction in the allogeneic human or xenogeneic mouse skin, injection of psoriatic immunocytes triggered psoriasis. To explore a potential mechanism to explain the lack of cytopathic effect by psoriatic T cells, immunostaining to detect inhibitory receptors normally present on NK cells was performed. These receptors include surface molecules that can inhibit NK cell proliferation, cytokine release, and/or cytotoxicity (ie, killer cell inhibitory receptors [KIRs]), as well as those that may activate NK cell cytotoxicity (ie, killer cell activating receptors [KARs]). The blood-derived psoriatic immunocytes in the skin graft expressed CD94, CD158a, CD158b, NKB1,and CD161. Furthermore, both hyperplastic human and murine keratinocytes express the major histocompatibility complex (MHC) class I-like CD1d protein, which has been shown to be a specific ligand of T cells expressing CD161 and other NK cell-associated receptors. CONCLUSIONS: Since several KIRs and KARs are known to recognize various class I MHC alleles, and because psoriasis inheritance and susceptibility has been linked to various class I MHC molecules, we propose a novel hypothesis in which the pathogenic T cells are postulated to express an assortment of KIRs and KARs. These interactions may produce direct activation without any exogenous antigen, and at the same time block the cytotoxic effector function of these activated immunocytes in this allogeneic and xenogeneic experimental setting. In addition, human T cells expressing CD161 may be capable of interacting with human and murine CDT1d expressed by the epidermal keratinocytes. These unexpected findings demonstrate that psoriasis is an immunological disease in which pathogenic T cells rather than epidermal keratinocytes are of primary importance. Functional studies will determine if targeting this previously overlooked population of immunocytes with blocking reagents will generate a novel immunotherapeutic strategic pathway for psoriasis, and whether disease susceptibility and/or incidence patterns can be explained by genetic abnormalities involving these ligand-receptor interactions.     

Human antimicrobial peptides LL-37 and human β-defensin-2 reduce viral replication in keratinocytes infected with varicella zoster virus

Background. There is mounting evidence that antimicrobial peptides have an important role in cutaneous defence, but the expression of these antimicrobial peptides in atopic eczema (AE) is still unclear. There are several families of antimicrobial peptides, including cathelicidins and human β‐defensins. Patients with AE are more susceptible to severe cutaneous viral infections, including varicella zoster virus (VZV). Aim. To characterize the functional activity of the antimicrobial peptides LL‐37 (human cathelicidin) and human β‐defensin (hBD)‐2 keratinocytes were infected with VZV, in a skin‐infection model. Methods. Flow‐cytometry analysis was used to investigate LL‐37 expression in normal human keratinocytes, and quantitative PCR was used to determine viral loads in infected HaCaT keratinocytes and B cells, with and without exogenous LL‐37 and hBD‐2. Results. LL‐37 expression was present in keratinocytes, and both exogenous LL‐37 and hBD‐2 significantly reduced VZV load in infected keratinocytes and B cells. Specific antibodies blocked the antiviral action exhibited by these antimicrobial peptides. Pre‐incubation of VZV with LL‐37, but not hBD‐2, further reduced VZV load. Conclusions. Both LL‐37 and hBD‐2 have an antiviral effect on VZV replication in the keratinocyte HaCaT cell line and in B cells, but their mechanism of action is different. Evidence of the relationship between antimicrobial peptide expression and higher susceptibility to infections in AE skin is still emerging. Developing novel antiviral therapies based on antimicrobial peptides may provide improved treatment options for patients with AE.     

5-aminolaevulinic acid and photodynamic therapy reduce HSV-1 replication in HaCat cells through an apoptosis-independent mechanism

Background: Photodynamic therapy (PDT) involves the use of a photosensitizing agent, which may require metabolic synthesis (i.e. a prodrug), followed by light activation. Numerous studies have advanced PDT as a means for treating bacteria, fungi and viruses. In this study, the photoinactivation of Herpes simplex virus type 1 (HSV‐1) in human keratinocytes using 5‐aminolaevulinic acid (5‐ALA) was investigated. Methods: HaCat cells were infected with HSV‐1 and treated with 5‐ALA to verify its antiviral effect during the stages of adsorption and penetration to host cells. Immunoblot analysis was used to estimate the effect of ALA–PDT on the production of viral proteins glycoprotein D (gD), infected cell proteins (ICP) 27 and virion protein (VP) 16. We also investigated whether the effect of ALA–PDT was associated with a cellular apoptotic mechanism through DNA fragmentation and the study of p53, PARP and caspase‐3 protein expression. Results: While the treatment of ALA–PDT after the viral adsorption period reduced HSV‐1 replication by about 70%, it did not act on the virus in the first phase of infection. The viral proteins' expressions were reduced by ALA–PDT treatments. There was no evidence of ALA–PDT‐induced apoptosis. Conclusion: Our data suggest that the target of photoinactivation appears to be viral replication and not a cellular response.     

IL‐1 signalling determines the fate of skin grafts expressing non‐self protein in keratinocytes

Please cite this paper as: IL‐1 signalling determines the fate of skin grafts expressing non‐self protein in keratinocytes. Experimental Dermatology 2010; 19 : 723–729. Abstract: 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‐1β 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‐1β 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‐1β‐associated skin graft rejection and induction of antigen‐specific CD8 T‐cell responses. Enhancing IL‐1β signalling, via blocking of the IL‐1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7‐associated cancers.