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

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.