Sjögren’s syndrome minor salivary gland CD4+ T cells associate with glandular disease features and have a germinal center T follicular helper transcriptional profile

Abstract

Abstract Objective 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 primary SS (pSS) and sicca subjects not meeting SS criteria (nSS). Methods SG biopsies of pSS and nSS subjects were evaluated for proportions (n=51 pSS, n=69 nSS) and absolute numbers (n=35 pSS, n=57 nSS) of CD4+ and CD8+ T cells. SG memory CD4+ T cells from focus score positive pSS (n=17) and focus score negative nSS subjects (n=15) were evaluated for gene expression by microarray. Differentially-expressed genes were identified and gene set enrichment and pathways analyses were performed. Results CD4+CD45RA− T cell frequencies 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, regardless of phenotype. 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 of pSS versus nSS subjects 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. Conclusions The proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis. SG memory CD4+ T cells express a germinal center Tfh profile.