A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.
| Publication Type | Academic Article |
| Authors | Wong H, Park K, Gola A, Baptista A, Miller C, Deep D, Lou M, Boyd L, Rudensky A, Savage P, Altan-Bonnet G, Tsang J, Germain R |
| Journal | Cell |
| Volume | 184 |
| Issue | 15 |
| Pagination | 3981-3997.e22 |
| Date Published | 06/21/2021 |
| ISSN | 1097-4172 |
| Keywords | Feedback, Physiological, Homeostasis, Lymphocyte Activation, T-Lymphocytes, Regulatory |
| 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 |
| PubMed ID | 34157301 |
| PubMed Central ID | PMC8390950 |