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  • Review Article
  • Published:

Selection and fine-tuning of the autoimmune T-cell repertoire

Nature Reviews Immunology volume 2, pages 487–498 (2002)Cite this article

Key Points

  • The ability of a self-reactive T cell to mount an autoaggressive response depends on the sensitivity (or functional avidity) that it has for the self-antigen.

  • Functional avidity is determined primarily by the affinity with which the self-peptide binds to the MHC molecule and the affinity of the T-cell receptor (TCR) for the resulting peptide–MHC complex, but alterations in the T-cell-signalling machinery can either raise or lower avidity.

  • High-avidity self-reactive T cells can escape negative selection if the self-antigen is not expressed in the thymus.

  • The self-peptide–MHC complex might be generated only at low levels owing to epitope destruction during antigen processing within the thymus. Low-affinity peptide–MHC binding might also allow high-avidity autoreactive T cells to escape negative selection and populate the periphery.

  • T cells remain sensitive to negative selection once in the periphery. Immunization with superagonist antigens results in the death of T cells that express high-affinity TCRs, which allows the selective expansion of T-cell populations that express low- to moderate-affinity TCRs and, therefore, have low to moderate functional avidity.

  • There is now increasing evidence that a T cell can modulate its functional avidity for antigen by altering the levels of molecules that control the TCR proximal-signalling events that lead to activation. This has become known as 'tuning'.

  • Tuning has been shown to take place during thymic development, which results in the reduced avidity of T cells that express transgenic TCRs of fixed affinity for peptide–MHC. This allows T cells to avoid negative selection by lowering their functional avidity.

  • Recent data indicate that T cells can also down-modulate their functional avidity after encountering neo-self-antigen in the periphery. Maintenance of this low-avidity state is dependent on continued exposure to the self-antigen.

  • These mechanisms of TCR-based selection and biochemical tuning prevent autoimmunity by maintaining the avidity of the normal self-reactive T-cell repertoire at a low level. The activation of these self-reactive T cells, therefore, requires levels of self-peptide–MHC complexes that might not be achieved under physiological conditions.

  • Activation of a pathological autoreactive response would, therefore, (probably) require a combination of factors that increase the level of self-antigen that is available and the avidity of the anti-self T-cell response.

Abstract

The immune system must avoid aggressive T-cell responses against self-antigens. But, paradoxically, exposure to self-peptides seems to have an important role in positive selection in the thymus and the maintenance of a broad T-cell repertoire in the periphery. Recent experiments have highlighted situations that allow high-avidity self-reactive T cells to avoid negative selection in the thymus. Accumulating evidence indicates that other, non-deleting mechanisms control the avidity with which T cells recognize self-antigens — a phenomenon that is known as 'tuning'. This might maximize the peripheral T-cell repertoire by allowing the survival of T cells that can respond to self, but only at concentrations that are not normally reached in vivo.

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Figure 1: Factors that affect functional T-cell avidity.
Figure 2: How self-reactive T cells might avoid negative selection in the thymus.
Figure 3: Model for avidity-based modulation of the peripheral T-cell repertoire.
Figure 4: How avidity-based peripheral tolerance might be broken.

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Acknowledgements

S.M.A. is a Medical Research Council Research Fellow. Additional work in our laboratories is funded by grants from The Wellcome Trust.

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Authors and Affiliations

  1. Institute of Cell, Animal and Population Biology, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JT, UK

    Stephen M. Anderton

  2. Department of Pathology and Microbiology, University of Bristol Medical School, University Walk, Bristol, BS8 1TD, UK

    David C. Wraith

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  1. Stephen M. Anderton
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Correspondence to Stephen M. Anderton.

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DATABASES

Entrez

moth cytochrome c

PCC

LocusLink

AEP

CD3

CD3 ζ-chain

CD4

CD5

CD8

CD28

CD45

CD74

CD80

CD86

CTLA4

H2-M

HLA-DM

ICAM1

LFA1

MBP

p56 LCK

PLP

SHP1

Smcy

ZAP70

OMIM

multiple sclerosis

Glossary

NEGATIVE SELECTION

The deletion of self-reactive thymocytes in the thymus. Thymocytes that express T-cell receptors that strongly recognize self-peptide bound to self-MHC undergo apoptosis in response to the signalling that is generated by high-affinity binding.

ANERGY

A state of T cells that have been stimulated by their T-cell receptors in the absence of CD28 ligation. On restimulation, these T cells are unable to make interleukin-2 or to proliferate, even in the presence of co-stimulatory signals.

POSITIVE SELECTION

The maturation of immature CD4+CD8+ precursor thymocytes induced by T-cell receptor (TCR) signals that result from binding to self-peptide–MHC ligands on thymic epithelial cells. This process selects thymocytes that express TCRs that are able to interact with self-MHC.

PEPTIDE–MHC TETRAMERS

Recombinant MHC molecules can be engineered to contain the antigenic peptide of interest in their peptide-binding groove. Biotinylation, followed by incubation with fluorescently labelled streptavidin, generates tetrameric complexes. These can be used to stain T cells that express TCRs that are specific for that peptide–MHC complex. In general, the intensity of tetramer staining correlates directly with T-cell receptor affinity.

FETAL THYMIC ORGAN CULTURE

Removal of day 16 fetal thymi allows the analysis of antigen-driven positive- and negative-selection events during in vitro culture.

ACTIVATION-INDUCED CELL DEATH

(AICD). The apoptotic cell death of activated lymphocytes. It ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion. Defects in AICD result in lymphoproliferative diseases that are associated with autoimmune disorders.

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Anderton, S., Wraith, D. Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol 2, 487–498 (2002). https://doi.org/10.1038/nri842

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