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Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes

Nature Immunology volume 8, pages 388–397 (2007)Cite this article

Abstract

The molecular basis underlying the specificity of alloreactive T cells for peptide–major histocompatibility complex ligands has been elusive. Here we describe a screen of 60 I-Ek-alloreactive T cells and 83 naturally processed peptides that identified 9 reactive T cells. Three of the T cells responded to multiple, distinct peptides that shared no sequence homology. These T cells recognized each peptide–major histocompatibility complex ligand specifically and used a distinct constellation of I-Ek contact residues for each interaction. Our studies show that alloreactive T cells have a 'germline-encoded' capacity to recognize multiple, distinct ligands and thus show 'polyspecificity', not degeneracy. Our findings help to explain the high frequency of alloreactive T cells and provide insight into the nature of T cell specificity.

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Figure 1: Alloreactive T cells specific for I-Ek can be divided into two categories based on their response to CHO-Ek APCs.
Figure 2: Identification of 9 alloreactive T cells and 12 allostimulatory peptides.
Figure 3: Alloreactive T cells respond to their respective peptides in a typical dose-dependent way.
Figure 4: Alloreactive T cells can recognize multiple unrelated allopeptides in a very specific way.
Figure 5: Alloreactive T cells that respond to multiple peptides accommodate distinct peptides by interacting with different MHC residues.
Figure 6: Alloreactive T cells have different requirements for CD4 that depend on the sensitivity of the T cell for the peptide.
Figure 7: CHO-Ek-reactive alloreactive T cells have a degree of peptide specificity.

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Acknowledgements

We thank M. Davis for the I-Ek mutant CHO cell lines, D. Kreamalmeyer for maintenance of the mouse colony, J. Smith for assistance in the preparation of the manuscript, and T. Hansen, E. Unanue and S. Weber for critical review of the manuscript. Supported by the National Centers for Research Resources of the National Institutes of Health (2P41RR00954, for mass spectrometry measurements).

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, 63130, Missouri, USA

    Nathan J Felix, David L Donermeyer, Stephen Horvath, Anish Suri & Paul M Allen

  2. Department of Chemistry, Washington University, St. Louis, 63130, Missouri, USA

    James J Walters & Michael L Gross

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Correspondence to Paul M Allen.

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Supplementary information

Supplementary Fig. 1

Identification of allostimulatory peptide binding registers. (PDF 579 kb)

Supplementary Table 1

Naturally processed and presented I-Ek bound peptides. (PDF 73 kb)

Supplementary Table 2

Multiple peptide-reactive allo-T cells interact with different MHC residues for each allostimulatory peptide. (PDF 75 kb)

Supplementary Table 3

Priming mice prior to allostimulation does not bias the TCR repertoire. (PDF 66 kb)

Supplementary Methods (PDF 103 kb)

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Felix, N., Donermeyer, D., Horvath, S. et al. Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes. Nat Immunol 8, 388–397 (2007). https://doi.org/10.1038/ni1446

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