Title | A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | 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 |
Journal | Cell |
Date Published | 2021 Jun 17 |
ISSN | 1097-4172 |
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. |
DOI | 10.1016/j.cell.2021.05.028 |
Alternate Journal | Cell |
PubMed ID | 34157301 |
Submitted by bel2021 on July 20, 2021 - 12:15pm