A CD8+ T cell transcription signature predicts prognosis in autoimmune disease

McKinney, Eoín; Lyons, Paul; Carr, Edward J; Hollis, Jane; Jayne, David; Willcocks, Lisa; Koukoulaki, Maria; Brāzma, Alvis; Jovanović, Vojislav; Kemeny, David M.; Pollard, Andrew J.; MacAry, Paul A.; Chaudhry, Afzal; Smith, Kenneth G. C.

doi:10.1038/nm.2130

Cited by 331 publications

(295 citation statements)

References 35 publications

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“…Tsokos and colleagues have suggested that, in SLE, activated CD8 + T cells generate double-negative (DN) T cells that can provide help to anti-DNA-producing B cells and infiltrate the kidneys of patients with SLE (49,50). Recently, a genetic study has linked hyperactive CD8 + T cells to the poor prognosis of a subset of SLE patients (51).Therefore, CD8 + T cells may play an important pathogenic role in systemic as well as organ-specific diseases.…”

Section: Figure 16mentioning

confidence: 99%

Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

Peng¹,

Elkon²

2011

J. Clin. Invest.

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Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8 -/-mice spontaneously developed dermatitis associated with CD8 + T cell infiltration and striking activation of effector memory CD8 + T cells. CD8 + T cell responses to both exogenous and endogenous apoptotic cell-associated antigens were enhanced in Mfge8 -/-mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8 + T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8 -/-DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation.

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Section: Figure 16mentioning

confidence: 99%

Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

Peng¹,

Elkon²

2011

J. Clin. Invest.

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“…Examples are seen in cancer, where recently gene expression-based biomarkers have facilitated targeted chemotherapy but this is only recently being translated into autoimmunity, and in systemic vasculitis, a CD8 T cell transcriptomic profile has now been shown to predict prognosis in two distinct patient subgroups. 101,102 Such approaches are readily transferrable to investigation in ocular inflammatory disease.…”

Section: How Do We Harness Our Approaches?mentioning

confidence: 99%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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The blockbuster drug paradigm is under increasing scrutiny across the biopharmaceutical industry. Intraocular inflammation poses particular challenges to this, given the heterogeneity of conditions in the uveitis spectrum, and the increasing acknowledgement of individual patient and disease variance in underlying immune responses. This need has triggered a drive towards personalised and stratified medicine, supported and enabled as a result of continued development of both experimental models and molecular biological techniques and improved clinical classification. As such we have the ability now to systematically appraise at a genomic, transcriptomic, and proteomic level individual immunophenotype, and the promise that in the eye this can be augmented by in vivo immune imaging to identify individual immunopathology. With such advances all running in parallel, we are entering an era of experimental medicine that will facilitate early diagnosis, generate biomarkers for accurate prognostication, and enable the development of individualised and targeted therapies, which can progress rapidly into clinical practice.

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“…We recently observed that a common CD8 T cell transcriptional signature could be detected in 2 unrelated, autoimmune diseases -SLE and ANCA-associated vasculitis (AAV) -and that this predicted disease prognosis in both (15). UC and CD are not classi-cal autoimmune diseases, being thought to arise from an inappropriate immune response to gut microbiota, rather than to self antigens (16).…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis

Lee¹,

Lyons²,

McKinney³

et al. 2011

J. Clin. Invest.

276

258

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Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8 + T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation -pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4 + T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

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A CD8+ T cell transcription signature predicts prognosis in autoimmune disease

Cited by 331 publications

References 35 publications

Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis

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