The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction
Open accessAbstract
Tregs control various functions of effector T cells; however, where and how Tregs exert their immunomodulatory effects remain poorly understood. Here we developed a murine model of adoptive T cell therapy and found that Tregs induce a dysfunctional state in tumor-infiltrating CTLs that resembles T cell exhaustion and is characterized by low expression of effector cytokines, inefficient cytotoxic granule release, and coexpression of coinhibitory receptors PD-1 and TIM-3. Induction of CTL dysfunction was an active process, requiring local TCR signals in tumor tissue. Tregs infiltrated tumors only subsequent to Ag-dependent activation and expansion in tumor-draining LNs; however, Tregs also required local Ag reencounter within tumor tissue to induce CTL dysfunction and prevent tumor rejection. Multiphoton intravital microscopy revealed that in contrast to CTLs, Tregs only rarely and briefly interrupted their migration in tumor tissue in an Ag-dependent manner and formed unstable tethering-interactions with CD11c+ APCs, coinciding with a marked reduction of CD80 and CD86 on APCs. Activation of CTLs by Treg-conditioned CD80/86lo DCs promoted enhanced expression of both TIM-3 and PD-1. Based on these data, we propose that Tregs locally change the costimulatory landscape in tumor tissue through transient, Ag-dependent interactions with APCs, thus inducing CTL dysfunction by altering the balance of costimulatory and coinhibitory signals these cells receive.
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Cites
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
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“In the present study, we found that tumor-infiltrating Tregs promoted the rapid induction of a state of functional hyporesponsiveness in CTLs that was characterized by impaired cytokine secretion and cytotoxic granule release, as well as coexpression of the coinhibitory receptors PD-1 and TIM-3, hallmarks of what has…”
Molecular mechanisms of T cell co-stimulation and co-inhibition
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Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866
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Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4
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“Here we found that rapid downregulation of CD80 and CD86 on DCs (27, 28) occurred most effectively when Tregs encountered their cognate Ag on DCs in vitro.”
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The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Martinez, G. J., Pereira, R. M., Äijö, T., Kim, E. Y., Marangoni, F., Pipkin, M. E., Togher, S., Heissmeyer, V., Zhang, Y. C., Crotty, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.006 · Cited by 857
“In Vivo Tumor Model Single-cell suspensions from spleens and LNs of CL4 mice were pulsed with 10 mM HA515–523 peptide for 1 hr at 37 C, then cultured with 10 ng/ml murine rIL-12 for the first 2 days and 20 ng/ml murine rIL-2 for the following 5 days as previously described (Bauer et al., 2014).”
InfluentialSelf-citationKumagai, S., Koyama, S., Itahashi, K., Tanegashima, T., Lin, Y.-T., Togashi, Y., Kamada, T., Irie, T., Okumura, G., Kono, H., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.01.001 · Cited by 892
Metadata
- Authors
- Bauer, C. A., Kim, E. Y., Marangoni, F., Carrizosa, E., Claudio, N. M., & Mempel, T. R.
- Venue
- Journal of Clinical Investigation
- Published
- 2014-05-08
- Volume
- 124
- Issue
- 6
- Pages
- 2425-2440
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2169859344
- Cited by
- 238
- References
- 16
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Bauer, C. A., Kim, E. Y., Marangoni, F., Carrizosa, E., Claudio, N. M., & Mempel, T. R. (2014). Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. Journal of Clinical Investigation. https://doi.org/10.1172/jci66375
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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
