Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis

Chamith Y. Fonseka, Deepak A. Rao, Nikola C. Teslovich, Ilya Korsunsky, Susan K. Hannes, Kamil Slowikowski, Michael F. Gurish, Laura T. Donlin, James A. Lederer, Michael E. Weinblatt, Elena M. Massarotti, Jonathan S. Coblyn, Simon M. Helfgott, Derrick J. Todd, Vivian P. Bykerk, Elizabeth W. Karlson, Joerg Ermann, Yvonne C. Lee, Michael B. Brenner, Soumya Raychaudhuri*

*Corresponding author for this work

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15 Scopus citations

Abstract

High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27 HLA-DR+ effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10−3). The frequency of CD27 HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27 HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27 HLA-DR+ cells were associated with RA (meta-analysis P = 2.3 × 10−4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27 HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27 HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with T helper 1 (TH1)– and cytotoxicity-associated features and produced abundant interferon-g (IFN-g) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data.

Original languageEnglish (US)
JournalScience translational medicine
Volume10
Issue number463
DOIs
StatePublished - Oct 17 2018

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fonseka, C. Y., Rao, D. A., Teslovich, N. C., Korsunsky, I., Hannes, S. K., Slowikowski, K., Gurish, M. F., Donlin, L. T., Lederer, J. A., Weinblatt, M. E., Massarotti, E. M., Coblyn, J. S., Helfgott, S. M., Todd, D. J., Bykerk, V. P., Karlson, E. W., Ermann, J., Lee, Y. C., Brenner, M. B., & Raychaudhuri, S. (2018). Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis. Science translational medicine, 10(463). https://doi.org/10.1126/scitranslmed.aaq0305