Polyspecificity of T cell and B cell receptor recognition

doi:10.1016/j.smim.2007.02.012

Seminars in Immunology

Volume 19, Issue 4, August 2007, Pages 216-224

https://doi.org/10.1016/j.smim.2007.02.012 Get rights and content

Abstract

A recent workshop discussed the recognition of multiple distinct ligands by individual T cell and B cell receptors and the implications of this discovery for lymphocyte biology. The workshop recommends general use of the term polyspecificity because it emphasizes two fundamental aspects, the inherent specificity of receptor recognition and the ability to recognize multiple ligands. Many different examples of polyspecificity and the structural mechanisms were discussed, and the group concluded that polyspecificity is a general, inherent feature of TCR and antibody recognition. This review summarizes the relevance of polyspecificity for lymphocyte development, activation and disease processes.

Section snippets

Purpose of the workshop

A recent workshop at the Santa Fe Institute organized by E. Sercarz, I. Cohen and A. Perelson on “Degeneracy and Complexity in the Immune System” discussed the emerging realization that lymphocyte receptors recognize multiple distinct ligands and the implications of this discovery for many different aspects of T cell and B cell biology. Participants described their work on the characterization of peptide/MHC ligands (E. Sercarz, H. Eisen, C. Pinilla and D. Hafler), structural mechanisms of

Perspective

One of the implications of the clonal selection theory was that a given T cell is highly specific for a single “cognate” peptide/MHC ligand and that recognition of alternative ligands is a rare event. This view was based on the observation that a given T cell clone typically does not respond when tested against several other antigens and that small changes in a peptide can result in a loss of T cell recognition. T cell activation was thus thought to be the result of recognition of a single

Systematic identification of peptide ligands with limited sequence similarity

Polyspecificity was first systematically studied by considering the structural requirements for both MHC class II binding and TCR recognition of a myelin basic protein (MBP) peptide recognized by T cell clones isolated from multiple sclerosis (MS) patients [3], [7]. The analysis was based on the realization that peptide-binding motifs by MHC class II molecules were quite degenerate because multiple amino acid substitutions were tolerated at the two major anchor residues of the MBP peptide for

General features of TCR recognition

Crystal structures of TCR–peptide/MHC complexes have provided a molecular understanding of the mechanisms of TCR specificity [14], [15], [16]. The 2C TCR structure demonstrated a diagonal binding mode in which the TCR covers almost the entire MHC-embedded peptide [15]. Four TCR loops can contribute to peptide recognition, the centrally located hypervariable CDR3 loops and the germline-encoded CDR1 loops. Most TCRs exhibit exquisite specificity for one or a few peptide side chains at peptide

Thymic selection determines the degree of TCR specificity and degeneracy

To address the impact of thymic negative selection on TCR specificity, IA^b + 3 K reactive T cells were isolated from conventional C57BL/6 mice and mice severely deficient in negative selection. T cells from normal C57BL/6 mice were very sensitive to amino acid substitutions at many positions of the peptide and MHC. In contrast, T cells from negative selection limited mice had a much wider range of specificity requirements [27]. Some T cells were biased in needing specific amino acids of the IA^bα

Receptor editing by autoreactive B cells

Similar to immature T cells, a large fraction of immature B cells is self-reactive, suggesting that most randomly generated antigen receptors are autoreactive. This high degree of autoreactivity was predicted several years ago based on mathematical modeling [29]. Cloning of antibodies from immature human B cells and analysis of their reactivity has shown that ∼55–75% of developing B cells exhibit reactivity to several autoantigens. If tolerance were maintained solely by clonal elimination

Polyspecificity and disease—Autoimmunity and viral infections

Several examples of self-reactive T cells that recognize a series of microbial peptides were already described above. These T cell clones were selected using a particular antigen and thus represent only one facet of the self-reactive repertoire. CD4 T cells that proliferated in response to self-peptide/MHC complexes in the absence of deliberate addition of antigen were therefore cloned from normal donors. T cells that proliferated based on loss of CFSE fluorescence (CSFE^low) were single cell

Quantitative assessment of the peptide repertoire presented to CD8 T cells

The availability of complete genome sequences and knowledge of the requirements for peptide processing by the proteasome, peptide transport by TAP and peptide binding by MHC molecules now permits a quantitative assessment of the number of peptides in human and microbial proteomes that can be presented to CD8 T cells. MHC class I molecules present 9-mer peptides (8–11 mers) and analysis of the human proteome (∼30,000 proteins) demonstrated that the majority of 9-mers (76%) are unique in

Specificity versus degeneracy

There are now numerous examples of polyspecificity of TCR recognition, as discussed above, both for human and murine T cells, CD4 and CD8 T cell populations and for T cells initially selected with a microbial or self-antigen. At the same time, there is abundant evidence for an exquisite degree of TCR specificity because minor changes in a peptide can result in loss of TCR recognition. Such changes can be localized either to peptide residues that directly contact TCR loops or to peptide residues

Complexity in T cell biology and other biological systems

A T cell recognizes multiple different peptide/MHC ligands during its lifetime: these include self-peptide/MHC complexes during positive selection in the thymus, an outcome illustrative of the utility of degeneracy; endogenous self-peptide/MHC complexes that contribute to survival of a naïve T cell in the periphery; and potentially, microbial peptides during the course of an infection. In the latter case, the microbial peptides may activate a self-recognizing cell and cause autoimmunity if

The nomenclature discussion

Many different terms have been used to describe the finding that T cells can recognize multiple distinct peptide/MHC ligands, including molecular mimicry, flexibility, plasticity, cross-reactivity and degeneracy (Table 1). Molecular mimicry was widely used during the early stages of research in this field. However, it only relates to the specialized case in which T cells recognize both peptides from self- and microbial antigens and can thus not serve as a general term that covers the many other

Summary

The substantial progress in the field reported at this meeting report leads to the conclusion that recognition of multiple peptide/MHC ligands by each TCR is a general, inherent property of this receptor system relevant for many different aspects of T cell biology (Table 2). The workshop recommends general use of the term polyspecificity because it simultaneously captures the two essential features, the recognition of multiple peptide/MHC ligands as well as the remarkable ability of TCRs to

Acknowledgments

The authors would like to thank the Santa Fe Institute and Wayne Cote for hosting this workshop and Lindsey Harvey for help in organizing the workshop and this manuscript. The work in this paper was supported by NIH Grant # R13 AI068354-01, Human Frontiers Science Program Grant # RGP0010/2004 and the Santa Fe Institute.

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ReviewPolyspecificity of T cell and B cell receptor recognition

Abstract

Section snippets

Purpose of the workshop

Perspective

Systematic identification of peptide ligands with limited sequence similarity

General features of TCR recognition

Thymic selection determines the degree of TCR specificity and degeneracy

Receptor editing by autoreactive B cells

Polyspecificity and disease—Autoimmunity and viral infections

Quantitative assessment of the peptide repertoire presented to CD8 T cells

Specificity versus degeneracy

Complexity in T cell biology and other biological systems

The nomenclature discussion

Summary

Acknowledgments

Immunity

Cell

Cell

Mol Immunol

Curr Opin Immunol

Microbes Infect

Cell

Cell

Cell

Cell

Immunity

Trends Immunol

Immunity

Cell

Immunol Today

J Theor Biol

J Theor Biol

Immunol Today

Cell

Semin Immunol

Degenerate recognition of a dissimilar antigenic peptide by myelin basic protein-reactive T cells. Implications for thymic education and autoimmunity

J Immunol

Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity

Proc Natl Acad Sci USA

Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide

Nature

Review
Polyspecificity of T cell and B cell receptor recognition