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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.

Tissue-resident CD8 + T cells (CD8 + T RM ) populate lymphoid and non-lymphoid tissues after infections as first line of defense against re-emerging pathogens. To achieve host protection, CD8 + T RM have developed surveillance strategies that combine dynamic interrogation of pMHC complexes on local stromal and hematopoietic cells with long-term residency. Factors mediating CD8 + T RM residency include CD69, a surface receptor opposing the egress-promoting S1P1, CD49a, a collagen-binding integrin, and CD103, which binds E-cadherin on epithelial cells. Moreover, the topography of the tissues of residency may influence T RM retention and surveillance strategies. Here, we provide a brief summary of these factors to examine how CD8 + T RM reconcile constant migratory behavior with their long-term commitment to local microenvironments, with a focus on epithelial barrier organs and exocrine glands with mixed connective-epithelial tissue composition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stein, Ruef and Wissmann.)

It is well established that tissue macrophages and tissue-resident memory CD8 + T cells (T RM ) play important roles for pathogen sensing and rapid protection of barrier tissues. In contrast, the mechanisms by which these two cell types cooperate for homeostatic organ surveillance after clearance of infections is poorly understood. Here, we used intravital imaging to show that T RM dynamically followed tissue macrophage topology in noninflamed murine submandibular salivary glands (SMGs). Depletion of tissue macrophages interfered with SMG T RM motility and caused a reduction of interepithelial T cell crossing. In the absence of macrophages, SMG T RM failed to cluster in response to local inflammatory chemokines. A detailed analysis of the SMG microarchitecture uncovered discontinuous attachment of tissue macrophages to neighboring epithelial cells, with occasional macrophage protrusions bridging adjacent acini and ducts. When dissecting the molecular mechanisms that drive homeostatic SMG T RM motility, we found that these cells exhibit a wide range of migration modes: In addition to chemokine- and adhesion receptor-driven motility, resting SMG T RM displayed a remarkable capacity for autonomous motility in the absence of chemoattractants and adhesive ligands. Autonomous SMG T RM motility was mediated by friction and insertion of protrusions into gaps offered by the surrounding microenvironment. In sum, SMG T RM display a unique continuum of migration modes, which are supported in vivo by tissue macrophages to allow homeostatic patrolling of the complex SMG architecture., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Flotillin-1 (Flot1) is an evolutionary conserved, ubiquitously expressed lipid raft-associated scaffolding protein. Migration of Flot1-deficient neutrophils is impaired because of a decrease in myosin II-mediated contractility. Flot1 also accumulates in the uropod of polarized T cells, suggesting an analogous role in T cell migration. In this study, we analyzed morphology and migration parameters of murine wild-type and Flot1 -/- CD8 + T cells using in vitro assays and intravital two-photon microscopy of lymphoid and nonlymphoid tissues. Flot1 -/- CD8 + T cells displayed significant alterations in cell shape and motility parameters in vivo but showed comparable homing to lymphoid organs and intact in vitro migration to chemokines. Furthermore, their clonal expansion and infiltration into nonlymphoid tissues during primary and secondary antiviral immune responses was comparable to wild-type CD8 + T cells. Taken together, Flot1 plays a detectable but unexpectedly minor role for CD8 + T cell behavior under physiological conditions., (Copyright © 2019 by The American Association of Immunologists, Inc.)

CD8 + T cells have evolved as one of the most motile mammalian cell types, designed to continuously scan peptide-major histocompatibility complexes class I on the surfaces of other cells. Chemoattractants and adhesion molecules direct CD8 + T-cell homing to and migration within secondary lymphoid organs, where these cells colocalize with antigen-presenting dendritic cells in confined tissue volumes. CD8 + T-cell activation induces a switch to infiltration of non-lymphoid tissue (NLT), which differ in their topology and biophysical properties from lymphoid tissue. Here, we provide a short overview on regulation of organism-wide trafficking patterns during naive T-cell recirculation and their switch to non-lymphoid tissue homing during activation. The migratory lifestyle of CD8 + T cells is regulated by their actomyosin cytoskeleton, which translates chemical signals from surface receptors into mechanical work. We explore how properties of the actomyosin cytoskeleton and its regulators affect CD8 + T cell function in lymphoid and non-lymphoid tissue, combining recent findings in the field of cell migration and actin network regulation with tissue anatomy. Finally, we hypothesize that under certain conditions, intrinsic regulation of actomyosin dynamics may render NLT CD8 + T-cell populations less dependent on input from extrinsic signals during tissue scanning., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)