Key Points
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The available T-cell repertoire — which is modified by interactions with self-peptide–MHC complexes in the thymus and in peripheral tissues — is a key factor in the development of autoimmune disease.
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Autoimmunity has been proposed to arise owing to defects in peripheral T-cell tolerance, molecular mimicry or defects in regulatory T cells. In addition, this article outlines a new model for the development of autoimmunity by means of aberrant peripheral T-cell homeostasis.
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Alterations in T-cell-signalling components that affect T-cell inhibitory-signalling pathways or T-cell survival can promote the development of autoimmunity.
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The Cbl family of proteins have a negative regulatory role in T-cell signalling and have been linked to autoimmunity
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The phosphatidylinositol 3-kinase (PI3K) pathway, which includes phosphatase and tensin homologue (PTEN) and protein kinase B (PKB), promotes T-cell survival by interfering with many cell-death pathways, including Fas-mediated apoptosis.
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The forkhead transcription factor FKHRL1 is a downstream target of PKB signalling and potentially promotes T-cell survival by inhibiting the transcription of pro-apoptotic genes, such as Bim.
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The forkhead transcription factor FOXP3 is an important regulator of lymphocyte homeostasis, but not due to its association with the PI3K–PKB pathway. Mutations in FOXP3 correlate with the autoimmune phenotype of scurfy mice and the human autoimmune disease IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome).
Abstract
The genetic manipulation of mice has led to insights into the molecular mechanisms of autoimmune disease. Recent studies have begun to identify ways in which signalling cascades can be disrupted that preclude the development of autoimmunity. This review outlines a new model for the induction of T-cell-mediated autoimmune diseases. I highlight recent data that illustrate the ways in which the altered survival of T cells and defects in the inhibitory signalling pathways of T cells can contribute to autoimmunity.
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Acknowledgements
I thank J. Woodgett, P. Marrack and R. Yeung for insightful discussions, and H. Gu for sharing unpublished data. I also thank M. Gronski, D. Millar, R. Jones, L. Nguyen and M. Woo for reading the manuscript and R. Pileggi for invaluable support. Unfortunately, due to space constraints, many citations and explanations have been limited.
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Glossary
- LYMPHOPAENIC MICE
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A loss of both T and B cells, as is seen in SCID or Rag-deficient mice or in lethally irradiated mice.
- HYPERGAMMAGLOBULINAEMIA
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An increased level of immunoglobulins in the blood.
- THYROIDITIS
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Inflammation of the thyroid. Hashimoto's thyroiditis is an organ-specific autoimmune disease that is characterized by hypothyroidism and an inflammatory lymphocytic infiltrate.
- INFLAMMATORY BOWEL DISEASE
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(IBD). A group of chronic inflammatory disorders of unknown origin that involve the gastrointestinal tract. Includes Crohn's disease and ulcerative colitis.
- INSULIN-DEPENDENT DIABETES MELLITUS
-
(IDDM). Also known as juvenile-onset diabetes, this is a common endocrine disorder that results from the immune-mediated destruction of insulin-producing pancreatic β-islet cells.
- EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
-
(EAE). Inflammation of the brain and spinal cord that is generally induced by the administration of myelin basic protein or myelin oligodendrocyte glycoprotein and adjuvants to disease-susceptible strains of mice.
- LIPID RAFT
-
A cholesterol-rich region that provides ordered structure to the lipid bilayer and that is able to include or exclude specific signalling molecules and complexes.
- SYSTEMIC LUPUS ERYTHEMATOSUS
-
(SLE). A disease of unknown origin in which tissues and cells are damaged by the deposition of pathogenic antibodies and immune complexes. Patients generally have abnormal B- and T-cell function.
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Ohashi, P. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2, 427–438 (2002). https://doi.org/10.1038/nri822
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DOI: https://doi.org/10.1038/nri822
