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

Abstract

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression–based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice1,2. We show that transcriptional profiling of purified CD8+ T cells, which avoids the confounding influences of unseparated cells3,4, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels5, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction6. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8+ T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity.

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Figure 1: T cell gene expression identifies a previously unrecognized subgroup of subjects with AAV at increased risk of relapsing disease.
Figure 2: The CD8+ T cell signature that predicts prognosis in AAV defines analogous subgroups in SLE.
Figure 3: Similar subgroups can be identified in a healthy population, and the defining signature is composed of genes whose expression predominantly conforms to a bimodal distribution.
Figure 4: Poor prognosis in AAV correlates with overexpression of mRNAs encoding proteins associated with T cell survival and memory.

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Acknowledgements

We thank D. Fearon and J. Todd for critical review of the manuscript, T. Rayner, M. Kapushesky and M. Clatworthy for helpful discussions, K. Townsend for help with subject recruitment, H. Woffendin and T. Freeman for help with optimizing the custom array platform and A. Hatton and H. Ratlamwala for technical support, along with all subjects and clinicians involved in enrollment and clinical follow up. We are grateful to E. Clutterbuck, R. Lazarus and the volunteers at the Oxford Vaccine Group for their help with recruitment of healthy controls. This work was supported by the UK National Institute of Health Research, the Cambridge Biomedical Research Centre, the Wellcome Trust (Programme Grant number 083650/Z/07/Z), the UK Medical Research Council, the Evelyn Trust, Kidney Research UK and the National Medical Research Council of Singapore (grant reference IRG07nov089). E.F.M. holds a Wellcome Fellowship, and L.C.W. a Medical Research Council, Clinical Training Fellowship. K.G.C.S. is a Lister Prize Fellow and Khoo Oon Teik Professor of Nephrology at the National University of Singapore. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895).

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K.G.C.S. and P.A.L. designed the study and wrote the paper along with E.F.M. E.F.M. analyzed the data with help from A.B., carried out experiments and collected and analyzed clinical data along with J.L.H., M.K., D.R.W.J., L.C.W. and A.N.C. E.J.C. contributed to experiments in healthy control subjects along with A.J.P. and performed validation of microarray results. Singaporean data was collected and analyzed by V.J., D.M.K. and P.A.M. along with E.F.M., P.A.L. and K.G.C.S.

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Correspondence to Paul A Lyons or Kenneth G C Smith.

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Supplementary Figures 1–13, Supplementary Tables 1–7, Supplementary Methods and Supplementary Discussion (PDF 9203 kb)

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McKinney, E., Lyons, P., Carr, E. et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 16, 586–591 (2010). https://doi.org/10.1038/nm.2130

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