The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/359/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 359-370

Articles

Structural Evidence of T Cell Xeno-reactivity in the Absence of Molecular Mimicry

Rui Zhao*, Douglas J. Loftus{ddagger}, Ettore Appella{ddagger}, and Edward J. Collins*

From the * Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and the {ddagger} Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

The T cell receptor (TCR), from a xeno-reactive murine cytotoxic T lymphocyte clone AHIII12.2, recognizes murine H-2Db complexed with peptide p1027 (FAPGVFPYM), as well as human HLA-A2.1 complexed with peptide p1049 (ALWGFFPVL). A commonly proposed model (the molecular mimicry model) used to explain TCR cross-reactivity suggests that the molecular surfaces of the recognized complexes are similar in shape, charge, or both, in spite of the primary sequence differences. To examine the mechanism of xeno-reactivity of AHIII12.2, we have determined the crystal structures of A2/p1049 and Db/p1027 to 2.5 Å and 2.8 Å resolution, respectively. The crystal structures show that the TCR footprint regions of the two class I complexes are significantly different in shape and charge. We propose that rather than simple molecular mimicry, unpredictable arrays of common and differential contacts on the two class I complexes are used for their recognition by the same TCR.

Key Words: major histocompatibility complex • crystallography • xeno-reactivity • transplantation • T cell receptor

Address correspondence to Edward J. Collins, Dept. of Microbiology and Immunology, CB#7290, 804 M.E. Jones Bldg., University of North Carolina at Chapel Hill, NC 27599. Phone: 919-966-6869; Fax: 919-962-8103; E-mail: collins1{at}med.unc.edu

R. Zhao is supported by a postdoctoral fellowship from the Cancer Research Institute. E.J. Collins acknowledges the support from National Institutes of Health grants AI29324 and AI20288.

Abbreviations used: β2m, β2-microglobulin; CDR, complementarity determining region.


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