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Wong HS, Park K, Gola A, et al. A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell. 2021;184(15):3981-3997.e22doi: 10.1016/j.cell.2021.05.028.
Wong, H. S., Park, K., Gola, A., Baptista, A. P., Miller, C. H., Deep, D., Lou, M., Boyd, L. F., Rudensky, A. Y., Savage, P. A., Altan-Bonnet, G., Tsang, J. S., & Germain, R. N. (2021). A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell, 184(15), 3981-3997.e22. https://doi.org/10.1016/j.cell.2021.05.028
Wong, Harikesh S, et al. "A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells." Cell vol. 184,15 (2021): 3981-3997.e22. doi: https://doi.org/10.1016/j.cell.2021.05.028
Wong HS, Park K, Gola A, Baptista AP, Miller CH, Deep D, Lou M, Boyd LF, Rudensky AY, Savage PA, Altan-Bonnet G, Tsang JS, Germain RN. A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell. 2021 Jul 22;184(15):3981-3997.e22. doi: 10.1016/j.cell.2021.05.028. Epub 2021 Jun 21. PMID: 34157301; PMCID: PMC8390950.
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Cell. 2021 Jul 22;184(15):3981-3997.e22. doi: 10.1016/j.cell.2021.05.028. Epub 2021 Jun 21.

A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.

Cell

Harikesh S Wong, Kyemyung Park, Anita Gola, Antonio P Baptista, Christine H Miller, Deeksha Deep, Meng Lou, Lisa F Boyd, Alexander Y Rudensky, Peter A Savage, Grégoire Altan-Bonnet, John S Tsang, Ronald N Germain

Affiliations

  1. Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address: [email protected].
  2. Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA; Biophysics program, Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
  3. Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
  4. Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA; Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, 9052 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium.
  5. Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
  6. Howard Hughes Medical Institute, Immunology Program and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  7. Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  8. Immunodynamics Group, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  9. Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
  10. Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address: [email protected].

PMID: 34157301 PMCID: PMC8390950 DOI: 10.1016/j.cell.2021.05.028

Abstract

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.

Published by Elsevier Inc.

Keywords: CTLA-4; IL-2; IL-2Rα; apoptosis; autoimmunity; computational modeling; feedback control; immune homeostasis; quantitative tissue imaging; regulatory T cells

Conflict of interest statement

Declaration of interests A.Y.R. is a co-founder of Sonoma Biotherapeutics; he is an SAB member and reports personal fees from Sonoma Biotherapeutics, RAPT Therapeutics, and Vedanta Biosciences and hol

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