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bioRxiv · 10.1101/172403

Reverse Association Of Single Cells To Rheumatoid Arthritis Accounting For Mixed Effects Identifies An Expanded CD27- HLA-DR+ Effector Memory CD4+ T Cell Population

Fonseka, C. Y.·Rao, D. A.·Teslovich, N. C.·Hannes, S. K.·Slowikowski, K.·Gurish, M. F.·Donlin, L. T.·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.
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Abstract

AO_SCPLOWBSTRACTC_SCPLOWHigh dimensional single-cell analyses have dramatically 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 due to technical and inter-individual variation. Here we present Mixed effects modeling of Associations of Single Cells (MASC), a novel 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 confounds and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from 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 (OR = 1.7; p = 1.1 x 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 respond to immunosuppressive therapy. Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained [~]5-fold higher frequencies of CD27- HLA-DR+ cells, which comprised [~]10% of synovial CD4+ T cells. We find that CD27- HLA-DR+ cells are abundant producers of IFN-{gamma} and also express perforin and granzyme A at elevated levels. Thus MASC identified the expansion of a unique Th1 skewed effector T cell population with cytotoxic capacity in RA. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data.\n\nOO_SCPLOWNEC_SCPLOW SO_SCPLOWENTENCEC_SCPLOW SO_SCPLOWUMMARYC_SCPLOWMixed-effects regression of single cells identifies a cytotoxic Th1-like CD4+ T cell subset while accounting for inter-individual and technical variation.

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Fonseka, C. Y., Rao, D. A., Teslovich, N. C., Hannes, S. K., Slowikowski, K., Gurish, M. F., Donlin, L. T., 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.. 2017-08-04. Reverse Association Of Single Cells To Rheumatoid Arthritis Accounting For Mixed Effects Identifies An Expanded CD27- HLA-DR+ Effector Memory CD4+ T Cell Population. https://doi.org/10.1101/172403

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