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

   


Authors: 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.
Article Title: A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells
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. © 2021
Keywords: apoptosis; autoimmunity; ctla-4; il-2; regulatory t cells; il-2rα; immune homeostasis; feedback control; computational modeling; quantitative tissue imaging
Journal Title: Cell
Volume: 184
Issue: 15
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2021-07-22
Start Page: 3981
End Page: 3997.e22
Language: English
DOI: 10.1016/j.cell.2021.05.028
PUBMED: 34157301
PROVIDER: scopus
PMCID: PMC8390950
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85110723414&doi=10.1016%2fj.cell.2021.05.028&partnerID=40&md5=f860f7b9e6c304855cba13ddfb7e5d1f
Notes: Article -- Export Date: 2 August 2021 -- Source: Scopus
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MSK Authors
  1. Alexander Rudensky
    156 Rudensky
  2. Deeksha Deep
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