The Immunogenicity of a New Human Minor Histocompatibility Antigen Results from Differential Antigen Processing

doi:10.1084/jem.193.2.195

Published online 8 January 2001.

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© The Rockefeller University Press, 0022-1007/2001/1/195/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 2, January 15, 2001 195-206

Original Article

The Immunogenicity of a New Human Minor Histocompatibility Antigen Results from Differential Antigen Processing

Anthony G. Brickner^a, Edus H. Warren^c,d, Jennifer A. Caldwell^e, Yoshiki Akatsuka^c,d, Tatiana N. Golovina^f, Angela L. Zarling^a, Jeffrey Shabanowitz^e, Laurence C. Eisenlohr^f, Donald F. Hunt^b,e, Victor H. Engelhard^a, and Stanley R. Riddell^c,d
^a Department of Microbiology, Beirne B. Carter Center for Immunology Research,
^b Department of Pathology, University of Virginia, Charlottesville, Virginia 22908
^c Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
^d University of Washington, Seattle, Washington 98195
^e Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
^f Department of Microbiology and Immunology and the Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Correspondence to: Victor H. Engelhard, Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Center, MR4 Bldg., Box 4012, Charlottesville, VA 22908. Tel:804-924-2423 Fax:804-924-1221 E-mail:vhe{at}virginia.edu.

Minor histocompatibility antigens (mHAgs) present a significantimpediment to organ and bone marrow transplantation betweenHLA-identical donor and recipient pairs. Here we report theidentification of a new HLA-A*0201–restricted mHAg, HA-8.Designation of this mHAg as HA-8 is based on the nomenclatureof Goulmy (Goulmy, E. 1996. Curr. Opin. Immunol. 8:75–81).This peptide, RTLDKVLEV, is derived from KIAA0020, a gene ofunknown function located on chromosome 9. Polymorphic allelesof KIAA0020 encode the alternative sequences PTLDKVLEV and PTLDKVLEL.Genotypic analysis demonstrated that the HA-8–specificcytotoxic T lymphocyte (CTL) clone SKH-13 recognized only cellsthat expressed the allele encoding R at P1. However, when PTLDKVLEVwas pulsed onto cells, or when a minigene encoding this sequencewas used to artificially translocate this peptide into the endoplasmicreticulum, it was recognized by CTLs nearly as well as RTLDKVLEV.This indicates that the failure of CTLs to recognize cells expressingthe PTLDKVLEV-encoding allele of KIAA0020 is due to a failureof this peptide to be appropriately proteolyzed or transported.Consistent with the latter possibility, PTLDKVLEV and its longerprecursors were transported poorly compared with RTLDKVLEV bytransporter associated with antigen processing (TAP). Thesestudies identify a new human mHAg and provide the first evidencethat minor histocompatibility differences can result from thealtered processing of potential antigens rather than differencesin interaction with the relevant major histocompatibility complexmolecule or T cell receptor.

Key Words: minor histocompatibility antigens, antigen processing, graftversus host disease, transplantation, Fourier transform massspectrometry

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