Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool

Klann, Jane; Remedios, Kelly A.; Kim, Stephanie H.; Metz, Patrick J.; Lopez, Justine; Mack, Lauren; Zheng, Ye; Ginsberg, Mark H.; Petrich, Brian G.; Chang, John T.

doi:10.4049/jimmunol.1601165

Cited by 34 publications

(32 citation statements)

References 58 publications

(72 reference statements)

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“…The resulting changes in lymphocyte–APC interaction are likely to have far-reaching effects. For example, loss of talin has recently been found to perturb regulatory T cell homeostasis ( 69 ). With respect to costimulatory signaling, molecules such as Rap1, FAK, and Pyk2 that regulate the function of clutch proteins may be involved.…”

Section: Discussionmentioning

confidence: 99%

Integrins Modulate T Cell Receptor Signaling by Constraining Actin Flow at the Immunological Synapse

et al. 2018

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Full T cell activation requires coordination of signals from multiple receptor–ligand pairs that interact in parallel at a specialized cell–cell contact site termed the immunological synapse (IS). Signaling at the IS is intimately associated with actin dynamics; T cell receptor (TCR) engagement induces centripetal flow of the T cell actin network, which in turn enhances the function of ligand-bound integrins by promoting conformational change. Here, we have investigated the effects of integrin engagement on actin flow, and on associated signaling events downstream of the TCR. We show that integrin engagement significantly decelerates centripetal flow of the actin network. In primary CD4+ T cells, engagement of either LFA-1 or VLA-4 by their respective ligands ICAM-1 and VCAM-1 slows actin flow. Slowing is greatest when T cells interact with low mobility integrin ligands, supporting a predominately drag-based mechanism. Using integrin ligands presented on patterned surfaces, we demonstrate that the effects of localized integrin engagement are distributed across the actin network, and that focal adhesion proteins, such as talin, vinculin, and paxillin, are recruited to sites of integrin engagement. Further analysis shows that talin and vinculin are interdependent upon one another for recruitment, and that ongoing actin flow is required. Suppression of vinculin or talin partially relieves integrin-dependent slowing of actin flow, indicating that these proteins serve as molecular clutches that couple engaged integrins to the dynamic actin network. Finally, we found that integrin-dependent slowing of actin flow is associated with reduction in tyrosine phosphorylation downstream of the TCR, and that this modulation of TCR signaling depends on expression of talin and vinculin. More generally, we found that integrin-dependent effects on actin retrograde flow were strongly correlated with effects on TCR signaling. Taken together, these studies support a model in which ligand-bound integrins engage the actin cytoskeletal network via talin and vinculin, and tune TCR signaling events by modulating actin dynamics at the IS.

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Section: Discussionmentioning

confidence: 99%

Integrins Modulate T Cell Receptor Signaling by Constraining Actin Flow at the Immunological Synapse

et al. 2018

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“…LFA-1 crosstalk with Notch signaling has been shown to induce IFNγ production and re-enforce Th1 cell functions suggesting that LFA-1 engagement with tissue resident APCs will further strengthen T cell differentiation ( 103 ). Similarly, Tregs have been shown to require talin and LFA-1 activation to induce IL-2Rα upregulation, which is required for Treg function ( 104 , 105 ). Additionally, we recently demonstrated that an intracellular pool of LFA-1 is relocalized to the cell surface upon initial T/APC interactions and plays a key role in T cell memory development ( 76 ).…”

Section: Lfa-1 and T Cell Activationmentioning

confidence: 99%

LFA-1 in T Cell Migration and Differentiation

2018

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Maintenance of homeostatic immune surveillance and development of effective adaptive immune responses require precise regulation of spatial and temporal lymphocyte trafficking throughout the body to ensure pathogen clearance and memory generation. Dysregulation of lymphocyte activation and migration can lead to impaired adaptive immunity, recurrent infections, and an array of autoimmune diseases and chronic inflammation. Central to the recruitment of T cells, integrins are cell surface receptors that regulate adhesion, signal transduction, and migration. With 24 integrin pairs having been discovered to date, integrins are defined not only by the composition of the heterodimeric pair but by cell-type specific expression and their ligands. Furthermore, integrins not only facilitate adhesion but also induce intracellular signaling and have recently been uncovered as mechanosensors providing additional complexity to the signaling pathways. Among several leukocyte-specific integrins, lymphocyte function-associated antigen-1 (LFA-1 or αLβ2; CD11a/CD18) is a key T cell integrin, which plays a major role in regulating T cell activation and migration. Adhesion to LFA-1’s ligand, intracellular adhesion receptor 1 (ICAM-1) facilitates firm endothelium adhesion, prolonged contact with antigen-presenting cells, and binding to target cells for killing. While the downstream signaling pathways utilized by LFA-1 are vastly conserved they allow for highly disparate responses. Here, we summarize the roles of LFA-1 and ongoing studies to better understand its functions and regulation.

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“…33 TLN1 encodes a cytoskeletal protein, talin-1, that has been implicated in phagocytosis, as well as regulates T cell proliferation and functions. 34, 35…”

Section: Resultsmentioning

confidence: 99%