Exocrine gland–resident memory CD8 ⁺ T cells use mechanosensing for tissue surveillance

Abstract

Tissue-resident CD8 + T cells (T RM ) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that T RM lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland T RM autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland T RM locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca 2+ signaling pathway. By contrast, naïve CD8 + T cells or T RM surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland T RM scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.

DOCK8 regulates a mechanosensitive actin redistribution that maintains immune cell cohesion and protects the nucleus during migration

“…It was recently shown that mechanical input leads to transcriptional changes in T cells [84][85][86] . Moreover, stiffness sensing by effector T cells is a critical driver of the differentiation of tissue resident memory T cells, and confinement-induced motility plays a role in antigen surveillance by T cells in the salivary gland 44,85 . Overall, defining the signaling axes which impact the ability of T cells to migrate through and establish residence in confined tissue environments may provide a therapeutic opportunity to modulate the migration to, and survival within, tissues where T cell surveillance is undesirable, for instance in autoimmunity.…”

“…As the appearance of the central F-actin cloud was only seen under confinement, we next asked whether this mechanosensitive F-actin response would be modulated by the rigidity of confining agar. To address this, we titrated the percent agarose from 0.5 to 2% to increase the degree of mechanical load 44 . Indeed, the fluorescence intensity at the cell centroid of F-actin scaled with the percent agarose in WT T cells (Fig.…”