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  • Review Article
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Specificity of T-cell alloreactivity

Nature Reviews Immunology volume 7, pages 942–953 (2007)Cite this article

Key Points

  • A high frequency of T cells are alloreactive and are involved in transplant rejection and graft-versus-host disease (GVHD).

  • Many alloreactive T cells are much more peptide specific than previously thought, and few if any recognize only the MHC molecule.

  • Alloreactive T cells are polyspecific, being able to recognize multiple distinct peptide–MHC complexes. This provides a potential explanation for the high frequency of allorecognition.

  • Structural studies of T-cell receptor (TCR)–peptide–MHC complexes reveal that alloreactive TCRs bind to peptide–MHC molecules in conventional ways and appear to exhibit similar diverse binding modes as conventional T cells.

  • There is no single set of molecular interactions that reveals a germline-encoded preference of TCRs to bind MHC molecules, but there may be conserved contacts that differ for each TCR variable (V) region and MHC allele.

  • Histocompatibility responses are important for marine colonial tunicates, allowing them to reject parasitic stem cells, but there is no selective advantage for alloreactivity in vertebrates. For vertebrates, alloreactivity may simply be the consequence of an inherent affinity of the TCR for the MHC molecule and a conserved surface among MHC alleles.

Abstract

T-cell alloreactivity is a well-established phenomenon, but its molecular basis has remained enigmatic. Although there are differences between T-cell recognition of conventional and allogeneic antigens, it has become increasingly clear that they share many similarities. Recent insights into the specificity of the T-cell receptor (TCR) for peptide and the seeming intrinsic affinity of the TCR for the surface of the MHC molecule have provided a better understanding of how the TCR and peptide–MHC complexes interact. Here, we highlight the similarities and differences between conventional and allogeneic recognition of TCR–peptide–MHC complexes, and discuss how our view of allorecognitionhas changed, as well as the implications for TCR specificity and T-cell development.

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Figure 1: T-cell recognition of conventional and allogeneic complexes.
Figure 2: MHC polymorphisms affect TCR interaction with the peptide–MHC surface.
Figure 3: Thymic selection eliminates the most-reactive and least-reactive TCRs.
Figure 4: Crosstalk between MHC class I and class II antigen-processing pathways.
Figure 5: The TCR may accommodate different peptides by making small adjustments to its interaction with the peptide–MHC complex.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Nathan J. Felix & Paul M. Allen

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  1. Nathan J. Felix
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Correspondence to Paul M. Allen.

Supplementary information

Supplementary information S1 (table)

TCR–peptide–MHC structures discussed in this review. (PDF 187 kb)

Related links

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DATABASES

RCSB Protein Data Bank

2C–EQYKFYSV–H-2Kbm3

BM3.3–INFDFNTI–H-2Kb

BM3.3–RGYVYQGL–H-2Kb

ENPVVHFFKNIVTPR–HLA-DR2b

EPLPQGQLTAY–HLA-B*3501

FLRGRAYGL–HLA-B8

KB5-C20–KVITFIDL–H-2Kb

LPEPLPQGQLTAY–HLA-B*3508

PKYVKQNTLKLAT–HLA-DR1

PKYVKQNTLKLAT–HLA-DR4

QLSPFPFDL–H-2Ld

SIYRYYGL–H-2Kb

Glossary

Self MHC molecules

This term refers to those MHC molecules that are encoded in an individual's genome and that are expressed by an individual's own antigen-presenting cells. These should be distinguished from the distinct donor- or graft-derived MHC alleles, which we refer to here as allogeneic MHC molecules.

Conventional immune response

An immune response directed against peptides presented by self MHC molecules is frequently referred to as a conventional immune response. We adopt this terminology here to distinguish these immune responses from those directed against peptides presented by allogeneic MHC molecules (alloresponses).

Self tolerance

Tolerance to an individual's own antigens that is achieved through both central and peripheral tolerance mechanisms including T-cell deletion, anergy and immune regulation. Without both central- and peripheral-tolerance mechanisms the immune system would be unable to distinguish self from foreign, resulting in autoimmunity.

Alloreactivity

An immune response to allograft transplantation that is directed against allelic differences between the host and donor. For the purposes of this Review we focus almost entirely on T-cell receptor recognition of peptide–allogeneic-MHC complexes; although alloreactivity also includes B-cell-mediated responses and innate immune responses to allelic differences between host and donor. In addition, alloreactivity can occur as host-versus-donor or donor-versus-host responses (as occurs in graft-versus-host disease).

Graft-versus-host disease

(GVHD). An immune response mediated by donor T cells contained in a transplanted allograft and directed against the recipient. GVHD is not associated with solid-organ transplantation, but can occur with bone-marrow or haematopoietic stem-cell transplants.

Degeneracy

In the context of T-cell recognition of antigen, degeneracy refers to a situation in which there is a decrease in the number and strength of the interactions between the TCR and the bound peptide. As a result, there is less specificity for the bound peptide.

Molecular mimicry

A term used to describe what happens when a T-cell receptor recognizes a microbial peptide that is structurally similar to a self peptide. The immune response initially directed at the microbial peptide spreads to tissues presenting the crossreactive self peptide, resulting in autoimmunity.

Polyspecificity

A recently suggested term to describe the ability of a single receptor (for example, a T-cell receptor or antibody) to recognize multiple unique ligands while maintaining a high degree of specificity for each ligand.

MHC class I tetramers

A tetrahedral complex artificially generated by joining four MHC class I molecules with a peptide of interest and β2-microglobulin. Because of their ability to interact with multiple T-cell recpetors (TCRs) at once, these tetramers are useful tools to detect specific binding despite the low affinity of individual TCR–peptide–MHC interactions.

Peptide libraries

A random mixture of peptides generated by mixing all 20 amino acids (or a subset thereof) at single or multiple peptide residue positions during the synthesis process. The resulting peptide pool will contain a mixture of peptides of which the theoretical complexity is determined by the number of positions at which substitutions were allowed and by the number of substitutions allowed at each position. The generation of a peptide library is an efficient means to obtain a large pool of peptides without individually synthesizing each member of the peptide pool.

Peptide mimotopes

A term generally used to refer to synthetic peptides of which the sequences have been empirically chosen based on their ability to mimic the response to the wild-type (and often unknown) peptide.

Direct and indirect allorecognition

The T-cell-mediated immune response to allogeneic tissues or grafts can occur through direct recognition of peptide–allogeneic-MHC complexes by host T-cell receptors or by indirect recognition of donor antigens captured by host antigen-presenting cells and presented as allogeneic-peptide–self-MHC complexes.

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Felix, N., Allen, P. Specificity of T-cell alloreactivity. Nat Rev Immunol 7, 942–953 (2007). https://doi.org/10.1038/nri2200

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