High Frequency of Terminally Differentiated CD8+ T Cells Characterize Systemic Lupus Erythematosus Patients with Renal Involvement

Nataly Manjarrez-Orduño¹, Laurence Menard¹, Julie Carman¹, Suzanne Suchard¹, Francesca Casano¹, Deborah Lee¹, Sium Habte¹, Sherif Daouti², Selena Kansal³, Dana Banas³, Can Jiang³, Dawn Stetsko³, Mark Cunningham³, Vivek Jayaswal⁴, Somnath Bandyopadhyay³, Sarah Hu³, Richard A. Furie⁵ and Steven G. Nadler⁶, ¹Discovery Translational Sciences Group, Bristol-Myers Squibb, Princeton, NJ, ²Bristol-Myers Squibb, Princeton, NY, ³Bristol-Myers Squibb, Princeton, NJ, ⁴Biocon Bristol-Myers Squibb Research Center, Bangalore, India, ⁵Division of Rheumatology, Northwell Health, Great Neck, NY, ⁶Immunosciences Translational Research, Bristol-Myers Squibb, Princeton, NJ

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: biomarkers and nephritis, CD8 cells, Lupus

Session Information

Date: Tuesday, November 15, 2016

Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: SLE is a highly heterogeneous disease. The identification of disease subtypes with different pathological mechanisms is crucial to identify subjects with different disease progression who may have differential responses to treatment. Since CD8+ T cell exhaustion has been associated with better clinical outcomes, we decided to focus on the CD8+ T cell subpopulations in lupus patients.

Methods: We analyzed 50 SLE patients under standard of care from a single clinical center (Northwell Health Division of Rheumatology). For every patient, we obtained a heparinized blood sample and one PAXgene tube. At the time of phlebotomy, we collected SLEDAI, clinical manifestations and autoantibodies. We used an open population cohort as controls. All protocols were approved by the IRB at NorthWell Health. Whole blood was used for CD8⁺ T cell phenotyping by flow cytometry, and PBMC were used for phospho-signaling and intracellular cytokine staining. The PAXgene tube was used for mRNA extraction and gene expression on an Affymetrix U-129 chip. The data from the gene expression study was used to evaluate gene modules (1). All statistical analysis were performed on JMP10 following published recommendations(2).

Results: Terminally differentiated CD8⁺ T cells are significantly increased in a subset of lupus patients (and confirmed in a second, independent cohort). Importantly, this increase in terminally differentiated CD8⁺ T cells is particularly noticeable in lupus patients with a history of lupus nephritis (p<0.05). SLE patients with higher proportions of terminally differentiated CD8⁺ T cells have i) higher levels of basal pAKT, ii) a lower capacity to induce pAKT upon CD3/CD28 stimulation iii) a higher proportion of cells that produce IFNg upon stimulation and iv) higher titers of ANA and anti-RNP70 autoantibodies. Importantly, the fraction of terminally differentiated CD8⁺cells that is quantifiable by flow cytometry correlates with a genomic signature of cytotoxic activity.

Conclusion: A subset of SLE patients, with a history of lupus nephritis are characterized by a high fraction of terminally differentiated CD8+ T cells and associated secretion of INFg. These data suggest that terminally differentiated CD8+ T cells may drive disease in LN patients and may benefit from therapies that block CD8⁺T cell activation.

1. L. Chiche et al., Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis & rheumatology (Hoboken, N.J.) 66, 1583-1595 (2014).

2. S. Lydersen, Statistical review: frequently given comments. Annals of the rheumatic diseases 74, 323-325 (2015).

Disclosure: N. Manjarrez-Orduño, Bristol-Myers Squibb, 3,Bristol-Myers Squibb, 1; L. Menard, Bristol-Myers Squibb, 3,Bristol-Myers Squibb, 1; J. Carman, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; S. Suchard, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; F. Casano, Bristol-Myers Squibb, 3,Bristol-Myers Squibb, 1; D. Lee, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; S. Habte, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; S. Daouti, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; S. Kansal, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; D. Banas, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; C. Jiang, Bristol-Myers Squibb, 3; D. Stetsko, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; M. Cunningham, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; V. Jayaswal, Biocon Bristol-Myers Squibb, 3; S. Bandyopadhyay, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; S. Hu, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; R. A. Furie, Bristol-Myers Squibb, 2,Bristol-Myers Squibb, 5; S. G. Nadler, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3.

To cite this abstract in AMA style:

Manjarrez-Orduño N, Menard L, Carman J, Suchard S, Casano F, Lee D, Habte S, Daouti S, Kansal S, Banas D, Jiang C, Stetsko D, Cunningham M, Jayaswal V, Bandyopadhyay S, Hu S, Furie RA, Nadler SG. High Frequency of Terminally Differentiated CD8+ T Cells Characterize Systemic Lupus Erythematosus Patients with Renal Involvement [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/high-frequency-of-terminally-differentiated-cd8-t-cells-characterize-systemic-lupus-erythematosus-patients-with-renal-involvement/. Accessed .

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