The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we ...investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals.
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•T cell cytotoxicity correlates with the exertion of mechanical force•Force exertion is associated with enhanced perforin pore formation on the target cell•Cell tension promotes perforin pore formation•Cytotoxic T cells spatiotemporally coordinate force exertion and perforin release
Cytotoxic T cells exert mechanical force against target cells through the immunological synapse. This potentiates target cell destruction by enhancing the pore-forming activity of the cytolytic molecule perforin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating ...cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αβ, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.
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•Cell transformation expands tissue-resident ILC1ls and ILTC1s•ILC1ls and ILTC1s share a distinct gene expression program•ILC1ls and ILTC1s exhibit potent cytotoxicity against tumor cells•IL-15 deficiency depletes ILC1ls and ILTC1s, resulting in tumor outgrowth
Cell transformation triggers a cancer immunosurveillance mechanism that engages tissue-resident lymphocytes derived from innate, TCRαβ, and TCRγδ lineages.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antitumor immunosurveillance is triggered by immune cell recognition of characteristic biochemical signals on the surfaces of cancer cells. Recent data suggest that the mechanical properties of ...cancer cells influence the strength of these signals, with physically harder target cells (more rigid) eliciting better, faster, and stronger cytotoxic responses against metastasis. Using analogies to a certain electronic music duo, we argue that the biophysical properties of cancer cells and their environment can adjust the volume and tone of the antitumor immune response. We also consider the potential influence of biomechanics-based immunosurveillance in disease progression and posit that targeting the biophysical properties of cancer cells in concert with their biochemical features could increase the efficacy of immunotherapy.
Immune responses are canonically triggered by biochemical signals. Many immunoreceptors, however, are mechanosensitive, and thus rely on the mechanical forces generated at cell-to-cell contacts to achieve full signaling capacity.Materials that mimic the mechanical properties of cells are useful for delineating the contribution of biophysical inputs to immune activation. As with all artificial systems, however, results must be interpreted with care.Mechanotransduction is particularly relevant for cytotoxic lymphocyte responses against metastatic cancer cells. As such, cytoskeletal regulators such as myocardin-related transcription factors (MRTFs) might serve as prognostic markers and targets for immune checkpoint blockade (ICB) therapy.Small-molecule therapies can induce mechanical reprogramming of tumor cells and elicit resistance mechanisms. In these cases, targeting emergent biophysical vulnerabilities of the tumor with immunotherapy might improve treatment outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The reorientation of the T cell microtubule-organizing center (MTOC) toward the antigen-presenting cell enables the directional secretion of cytokines and lytic factors. By single-cell ...photoactivation of the T cell antigen receptor, we show that MTOC polarization is driven by localized accumulation of diacylglycerol (DAG). MTOC reorientation was closely preceded first by production of DAG and then by recruitment of the microtubule motor protein dynein. Blocking DAG production or disrupting the localization of DAG impaired MTOC recruitment. Localized DAG accumulation was also required for cytotoxic T cell-mediated killing. Furthermore, photoactivation of DAG itself was sufficient to induce transient polarization. Our data identify a DAG-dependent pathway that signals through dynein to control microtubule polarity in T cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite decades of intensive research, T-cell activation has remained mysterious because of both the dizzying diversity of antigen recognition and the speed and comprehensiveness of the ...T-cell-receptor signalling network. Further progress will require new approaches and reagents that provide added levels of control. Photochemistry allows specific biochemical processes to be controlled with light and is well suited to mechanistic studies in complex cellular environments. In recent years, several laboratories have adopted approaches based on photoreactive peptide-major histocompatibility complex reagents in order to study T-cell activation and function with high precision. Here, I review these efforts and outline future directions for this exciting area of research.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which ...promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease.
•Metastatic cells with high MRTF activity are vulnerable to cytotoxic lymphocytes in vivo•Strong MRTF signaling is associated with responsiveness to immune checkpoint blockade•Cancer cells overexpressing MRTF induce stronger lymphocyte activation and cytotoxicity•MRTF makes cancer cells more stimulatory to lymphocytes by increasing their rigidity
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Myocardin-related transcription factors promote metastatic colonization by inducing cell spreading and migration. Tello-Lafoz et al. show that the cellular stiffening that accompanies this morphologic change triggers a mechanical form of immunosurveillance in which cytotoxic lymphocytes destroy the metastatic cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B ...lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self-ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
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