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J. Biol. Chem., Vol. 281, Issue 36, 26129-26135, September 8, 2006

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Sequential Proteolytic Processing of the Capsular Caf1 Antigen of Yersinia pestis for Major Histocompatibility Complex Class II-restricted Presentation to T Lymphocytes^*

Julie A. Musson, Margaret Morton, Nicola Walker, Helen M. Harper, Hesta V. McNeill, E. Diane Williamson, and John H. Robinson¹

From the Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, and Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom

We studied the mechanisms of antigen presentation of CD4 T cell epitopes of the capsular Caf1 antigen of Yersinia pestis using murine bone marrow macrophages as antigen presenting cells and T cell hybridomas specific for major histocompatibility complex (MHC) class II-restricted epitopes distributed throughout the Caf1 sequence. The data revealed diversity in the pathways used and the degrees of antigen processing required depending on the structural context of epitopes within the Caf1 molecule. Two epitopes in the carboxyl-terminal globular domain were presented by newly synthesized MHC class II after low pH-dependent lysosomal processing, whereas an epitope located in a flexible amino-terminal strand was presented by mature MHC class II independent of low pH and with no detectable requirement for proteolytic processing. A fourth epitope located between the two regions of Caf1 showed intermediate behavior. The data are consistent with progressive unfolding and cleavage of rCaf1 from the amino terminus as it traverses the endosomal pathway, the availability of epitopes determining which pool of MHC class II is preferentially loaded. The Caf1 capsular protein is a component of second generation plague vaccines and an understanding of the mechanisms and pathways of MHC class II-restricted presentation of multiple epitopes from this candidate vaccine antigen should inform the choice of delivery systems and adjuvants that target vaccines successfully to appropriate intracellular locations to induce protective immune responses against as wide a T cell repertoire as possible.

Received for publication, June 8, 2006

^* This work was supported by extramural research contracts from the Defence Science and Technology Laboratory, United Kingdom. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Tel.: 44-191-222-7866; Fax: 44-191-222-7736; E-mail: j.h.robinson{at}ncl.ac.uk.

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