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Journal of Virology, July 1999, p. 6166-6170, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Human Papillomavirus Type 16 E7 Oncoprotein Expressed in Peripheral Epithelium Tolerizes E7-Directed Cytotoxic T-Lymphocyte Precursors Restricted through Human (and Mouse) Major Histocompatibility Complex Class I Alleles

Tracy Doan,1 Karen Herd,1 Michael Street,1 Gregory Bryson,2 Germain Fernando,3 Paul Lambert,4 and Robert Tindle1,*

Sir Albert Sakzewski Virus Research Centre,1 and the Department of Paediatrics and Child Health and Department of Pathology,2 Royal Children's Hospital, Brisbane, Queensland 4029, and Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4021,3 Australia, and McCardle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 537064

Received 7 January 1999/Accepted 31 March 1999

Mice which coexpress human papillomavirus type 16 E7 and HLA A2.1 in peripheral squamous epithelium and thymic cortical epithelium are tolerant at the cytotoxic T-lymphocyte (CTL) level to E7 epitopes restricted through HLA A*0201 and H-2b (T. Doan, M. Chambers, M. Street, G. J. Fernando, K. Herd, P. Lambert, and R. Tindle, Virology 244:352-364, 1998). Here we used bone marrow-reconstituted radiation chimeras to distinguish whether E7-directed CTL tolerance was mediated peripherally by E7 expression in skin or centrally by E7 expression in thymus. In chimeric mice expressing E7 in skin and reconstituted with E7-naïve bone marrow and E7-naïve thymus, CTL responses to vaccine-administered E7 epitopes were not restored, i.e., the mice remained tolerant. In contrast, chimeric mice not expressing E7 in skin and reconstituted with E7-naïve bone marrow and E7-expressing thymus had full E7-directed CTL responses. These results demonstrate that E7 protein expression in peripheral squamous epithelium is sufficient to tolerize the E7-directed CTL precursor repertoire. The data have implications for E7-mediated tumorigenesis and for the development of E7-based immunotherapeutic strategies, since peripheral immunological tolerance of tumor-associated antigens may create a barrier to effective immunotherapy.

* Corresponding author. Mailing address: Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Herston Rd., Brisbane, Qld 4029, Australia. Phone: 61-7-3253-8716. Fax: 61-7-3253-1401. E-mail: r.tindle{at}mailbox.uq.edu.au.

Journal of Virology, July 1999, p. 6166-6170, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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