Sjögren's Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile

Michelle L Joachims; Kerry M Leehan; Mikhail G Dozmorov; Constantin Georgescu; Zijian Pan; Christina Lawrence; M Caleb Marlin; Susan Macwana; Astrid Rasmussen; Lida Radfar; David M Lewis; Donald U Stone; Kiely Grundahl; R Hal Scofield; Christopher J Lessard; Jonathan D Wren; Linda F Thompson; Joel M Guthridge; Kathy L Sivils; Jacen S Moore; A Darise Farris

doi:10.3390/jcm9072164

Sjögren's Syndrome Minor Salivary Gland CD4⁺ Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile

J Clin Med. 2020 Jul 8;9(7):2164. doi: 10.3390/jcm9072164.

Authors

Michelle L Joachims¹, Kerry M Leehan¹, Mikhail G Dozmorov¹, Constantin Georgescu¹, Zijian Pan¹, Christina Lawrence¹, M Caleb Marlin¹, Susan Macwana¹, Astrid Rasmussen¹, Lida Radfar², David M Lewis², Donald U Stone³, Kiely Grundahl¹, R Hal Scofield^{1

4

5}, Christopher J Lessard¹, Jonathan D Wren¹, Linda F Thompson¹, Joel M Guthridge¹, Kathy L Sivils¹, Jacen S Moore¹, A Darise Farris¹

Affiliations

¹ Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
² College of Dentistry, University of Oklahoma Health Sciences Center, 1201 N Stonewall Avenue, Oklahoma City, OK 73117, USA.
³ Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA.
⁴ Department of Medicine, University of Oklahoma Health Sciences Center, 1100 N Lindsay Avenue, Oklahoma City, OK 73104, USA.
⁵ Department of Veteran's Affairs Medical Center, 931 NE 13th Street, Oklahoma City, OK 73104, USA.

Abstract

To assess the types of salivary gland (SG) T cells contributing to Sjögren's syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4⁺ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4⁺ and CD8⁺ T cells. SG memory CD4⁺ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4⁺CD45RA^- T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8⁺CD45RA^- T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4⁺CD45RA^- T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4⁺CD45RA^- cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4⁺ T cells associate with key SS features, consistent with a central role in disease pathogenesis.

Keywords: T lymphocytes; salivary gland; sjögren’s syndrome; transcriptome.

Abstract

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