Review Article | Published:

Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

Nature Reviews Immunology volume 8, pages 545558 (2008) | Download Citation

Abstract

Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases and elevated IgE production. This causative association is counter-intuitive — immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-of-function changes. This Review details the genetic basis of partial T -cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.

Key points

  • Clinical severe T-cell immunodeficiencies (in many cases accompanied by deficiencies of other lymphocyte populations) are known to be caused by mutations in almost 40 different genes. These genes encode products vital for processes such as cytokine and T-cell receptor (TCR) signalling, V(D)J recombination and antigen presentation.

  • T-cell immunodeficiencies may not always be absolute, and in many cases an immunodeficient patient may also have symptoms of immune dysregulation, such as autoimmunity. In certain cases, identical mutations can cause severe or partial T-cell immunodeficiency, highlighting the complexity of pathogenesis.

  • For both severe and partial T-cell immunodeficiencies in humans, there are multiple genetic and/or phenotypic counterparts in mice, which are proving invaluable as tools to dissect cellular and biochemical mechanisms of these disorders.

  • Studies of these models have revealed that multiple T-cell tolerance mechanisms are population sensitive. These mechanisms, including thymic negative selection, peripheral suppression by FOXP3+ regulatory T cells and peripheral activation of effector T cells, show reduced efficacy at low T-cell population densities regardless of the properties of individual T cells.

  • Many common variant alleles (in genes such as PTPN22 (protein tyrosine phosphatase, non-receptor type 22) and IL7RA (interleukin-7 receptor α-chain)) have been reproducibly associated with multiple common autoimmune diseases. We propose that a proportion of such alleles (and also rare alleles not detected by genome-wide association studies) contribute to common autoimmune diseases by creating a state of partial T-cell immunodeficiency, which is insufficient in itself to promote autoimmunity but can synergize to promote the activation of self-reactive T cells.

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Acknowledgements

We thank C. Goodnow and K. Randal for stimulating discussions, and R. Cornall, L. Miosge and C. Goodnow for sharing unpublished data. This work is supported by the CJ Martin and RG Menzies Foundations (A.L.) and the Deutsche Forschungsgemeinschaft (A.E.).

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Affiliations

  1. John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.

    • Adrian Liston
    • , Anselm Enders
    •  & Owen M. Siggs
  2. Department of Immunology, University of Washington, Seattle, Washington 98195, USA.

    • Adrian Liston
  3. Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Owen M. Siggs

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Corresponding author

Correspondence to Adrian Liston.

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    Supplementary information

    Human genetic variants responsible for severe T-cell immunodeficiency

Glossary

Immunodeficiency

A state in which the capacity of the immune system to respond to infectious disease is compromised or completely absent.

Positive selection

One step in the process of T-cell differentiation in the thymus. T cells that express T-cell receptors with moderate to high affinity for self antigens receive a survival signal and continue to develop towards becoming double positive (CD4+CD8+) T cells. Positive selection occurs through antigens presented by resident stromal cells and dendritic cells in the thymic cortex and is followed by negative selection.

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T-cell and B-cell receptors.

APECED

(Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy syndrome). A rare human autoimmune disorder that is inherited in an autosomal recessive manner and is characterized by various endocrine deficiencies, chronic mucocutaneous candidiasis and ectodermal dystrophies. It is caused by several different mutations in the gene that encodes autoimmune regulator (AIRE).

IPEX

(Immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome). A disease caused by mutations in FOXP3 (forkhead box P3) and characterized by refractory enteritis and, in some patients, autoimmune endocrinopathies, autoimmune diabetes and thyroiditis.

Graft-versus-host disease

Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T cells recognizing the tissues of the recipient as foreign. This disease varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

Autoimmune thrombocytopaenia

A reduced number of circulating platelets, owing to increased immune-mediated clearance from the blood, predominantly in the spleen.

Graves' disease

A type of autoimmune disease in which autoantibodies produced by the immune system overstimulate the thyroid gland, causing hyperthyroidism.

N-ethyl-N-nitrosourea

(ENU). An ethylating chemical that produces a high rate of genome-wide point mutations at random in the germline.

Cre-LoxP technology

A site-specific recombination system. Two short DNA sequences (LoxP sites) are engineered to flank the target DNA. Expression of Cre recombinase leads to excision of the intervening sequence. Depending on the type of promoter, Cre can be expressed at specific times during development or in specific sets of cells.

Antinuclear antibodies

Autoantibodies generated against antigens within the nucleus, including DNA. They are indicative of systemic lupus erythematosus, but are also common in patients with rheumatoid arthritis, Sjogren's syndrome and other autoimmune diseases, and are rarely found in healthy individuals.

Negative selection

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

FOXP3+ regulatory T cells

A rare population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (FOXP3), and that have suppressive regulatory activity towards effector T cells and other immune cells. Absence or dysfunction of these cells is associated with severe autoimmunity.

γδ T cells

T cells that express a T-cell receptor consisting of a γ-chain and a δ-chain.

Immunogenic signalling

Signalling that results in immunity by enhancing the immune response. Immunogenic T-cell receptor signalling can be defined as signalling that increases the activation of effector T cells or reduces the activity of regulatory T cells.

Tolerogenic signalling

Signalling that results in the suppression of immunity or the induction of immune tolerance. Tolerogenic T-cell receptor signalling can be defined as signalling that reduces the activation of effector T cells or increases the activity of regulatory T cells.

Immunological synapse

A region that can form between two cells of the immune system in close contact. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.

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DOI

https://doi.org/10.1038/nri2336

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