The Journal of Immunology, Vol 155, Issue 6 2993-3001, Copyright © 1995 by American Association of Immunologists

ARTICLES

Intramolecular mimicry. Identification and analysis of two cross- reactive T cell epitopes within a single protein

DT Hagerty and PM Allen
Department of Medicine, Jewish Hospital of St. Louis, MO 63110, USA.

The recognition of peptide Ags by T cells through the TCR has exquisite specificity. Cross-reactive T cell responses have been described; however, the structural basis for these responses is not known. We show that two peptides derived from the same protein can exhibit sufficient structural homology, despite minimal structural identity, to elicit cross-reactive T cell responses. In addition, we explore the structural basis for cross-reactivity. T cell hybridomas recognizing PiM and PiZ allelic forms of human alpha 1-antitrypsin (hAAT) each recognized both PiM 205-220 and PiM 335-350. These two peptides possessed primary sequence identity at only two of 16 amino acid residues. Cross-reactive peptides also exhibited homology at the bulk T cell level because lymph node T cells primed with one peptide proliferated to the other peptide in vitro. Critical amino acids for the responding T cells were determined, and the core was transferred into the less reactive peptide in an attempt to increase homology by increasing sequence identity. Interestingly, as identity increased, homology decreased: peptides with the least primary sequence identity appeared most homologous to the T cells. These results have important implications for understanding the development of autoimmune diseases, and imply that minimal obvious primary sequence identity may be sufficient to initiate cross-reactive T cell responses. The ability of structurally dissimilar peptides to mimic each other when bound to a class II MHC molecule may also be important to the understanding of T development and autoimmunity.

This article has been cited by other articles:

				V. Voelter, N. Rufer, S. Reynard, G. Greub, R. Brookes, P. Guillaume, F. Grosjean, T. Fagerberg, O. Michelin, S. Rowland-Jones, et al. Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor Int. Immunol., August 1, 2008; 20(8): 1087 - 1096. [Abstract] [Full Text] [PDF]

				D. L. Donermeyer, K. S. Weber, D. M. Kranz, and P. M. Allen The Study of High-Affinity TCRs Reveals Duality in T Cell Recognition of Antigen: Specificity and Degeneracy J. Immunol., November 15, 2006; 177(10): 6911 - 6919. [Abstract] [Full Text] [PDF]

				E. Papp, P. Szaraz, T. Korcsmaros, and P. Csermely Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding {alpha}1-antitrypsin transgenic mice FASEB J, May 1, 2006; 20(7): 1018 - 1020. [Abstract] [Full Text] [PDF]

				T. Sandalova, J. Michaelsson, R. A. Harris, J. Odeberg, G. Schneider, K. Karre, and A. Achour A Structural Basis for CD8+ T Cell-dependent Recognition of Non-homologous Peptide Ligands: IMPLICATIONS FOR MOLECULAR MIMICRY IN AUTOREACTIVITY J. Biol. Chem., July 22, 2005; 280(29): 27069 - 27075. [Abstract] [Full Text] [PDF]

				B. Laugel, J. M. Boulter, N. Lissin, A. Vuidepot, Y. Li, E. Gostick, L. E. Crotty, D. C. Douek, J. Hemelaar, D. A. Price, et al. Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition J. Biol. Chem., January 21, 2005; 280(3): 1882 - 1892. [Abstract] [Full Text] [PDF]

				G. Wildner and M. Diedrichs-Mohring Differential recognition of a retinal autoantigen peptide and its variants by rat T cells in vitro and in vivo Int. Immunol., August 1, 2003; 15(8): 927 - 935. [Abstract] [Full Text] [PDF]

				S. K. Joshi, P. R. Suresh, and V. S. Chauhan Flexibility in MHC and TCR Recognition: Degenerate Specificity at the T Cell Level in the Recognition of Promiscuous Th Epitopes Exhibiting No Primary Sequence Homology J. Immunol., June 1, 2001; 166(11): 6693 - 6703. [Abstract] [Full Text] [PDF]

				S. M. Varga, L. K. Selin, and R. M. Welsh Independent Regulation of Lymphocytic Choriomeningitis Virus-Specific T Cell Memory Pools: Relative Stability of CD4 Memory Under Conditions of CD8 Memory T Cell Loss J. Immunol., February 1, 2001; 166(3): 1554 - 1561. [Abstract] [Full Text] [PDF]

				M. P. Rudolf2 3, A. W. Zuercher2 4, A. Nechansky, C. Ruf, M. Vogel, S. M. Miescher, B. M. Stadler, and F. Kricek Molecular Basis for Nonanaphylactogenicity of a Monoclonal Anti-IgE Antibody J. Immunol., July 15, 2000; 165(2): 813 - 819. [Abstract] [Full Text] [PDF]

				E. Maverakis, J. T. Beech, S. S. Wilson, A. Quinn, B. Pedersen, and E. E. Sercarz T Cell Receptor Complementarity Determining Region 3 Length Analysis Reveals the Absence of a Characteristic Public T Cell Repertoire in Neonatal Tolerance: The Response in the "Tolerant" Mouse within the Residual Repertoire Is Quantitatively Similar but Qualitatively Different J. Exp. Med., February 21, 2000; 191(4): 695 - 702. [Abstract] [Full Text] [PDF]

				C. S. Wilson, J. M. Moser, J. D. Altman, P. E. Jensen, and A. E. Lukacher Cross-Recognition of Two Middle T Protein Epitopes by Immunodominant Polyoma Virus-Specific CTL J. Immunol., April 1, 1999; 162(7): 3933 - 3941. [Abstract] [Full Text] [PDF]

				T. Ono, T. P. DiLorenzo, F. Wang, A. M. Kalergis, and S. G. Nathenson Alterations in TCR-MHC Contacts Subsequent to Cross-Recognition of Class I MHC and Singly Substituted Peptide Variants J. Immunol., November 15, 1998; 161(10): 5454 - 5463. [Abstract] [Full Text] [PDF]

				O. Williams, R. Tarazona, A. Wack, N. Harker, K. Roderick, and D. Kioussis Interactions with multiple peptide ligands determine the fate of developing thymocytes PNAS, May 12, 1998; 95(10): 5706 - 5711. [Abstract] [Full Text] [PDF]