Integrin α7-Driven Senescence-Associated Follicular Helper T Cell Adhesion Induces Tertiary Lymphoid Structures in...

Senescence-associated follicular helper T (SA-Tfh) cells contribute to tertiary lymphoid structure (TLS) formation in autoimmune diseases, yet the mechanisms guiding their localization to glandular niches remain unclear. In the Nishiura (NI) Sjögren's disease (SjD) mouse model, we demonstrated that mouse SA-Tfh (mSA-Tfh; CD4⁺/PD-1⁺/CD153⁺) cells form TLSs specifically within the submandibular gland niche. We identified integrin α7 (ITGα7) expression in mSA-Tfh cells and examined its functional role. Adhesion of mSA-Tfh cells to laminin (LAM) α2/α3/α4 was inhibited by anti-ITGα7 IgG (E-2), and ITGα7-deficient mSA-Tfh cells had reduced adhesion to LAMα1/α2 compared with LAMα3/α4/α5. Osteopontin production by mSA-Tfh cells, either alone or via interactions with mB220⁺/PD-1⁺ cells, was suppressed by E-2, anti-LAMα4 IgG, and ITGα7 deficiency. In female NI mice, E-2 administration at 24 weeks reduced Greenspan grade 4 TLSs at 28 weeks by decreasing ITGα7⁺/CD153⁺ cell accumulation. mSA-Tfh infiltration into aged C57BL/6 mice was similarly diminished by ITGα7 or LAMα4 deficiency. In human SjD cohorts, ITGα7 expression positively correlated with CD153 expression (R² = 0.41) in peripheral lymphocytes and with LAMα4 expression (R² = 0.35) in salivary gland vasculature and ducts. These findings suggest that circulating ITGα7⁺ SA-Tfh cells adhere to the LAMα4⁺ glandular niche to promote TLS formation in SjD.