| First Author | Wong HS | Year | 2021 |
| Journal | Cell | Volume | 184 |
| Issue | 15 | Pages | 3981-3997.e22 |
| PubMed ID | 34157301 | Mgi Jnum | J:308493 |
| Mgi Id | MGI:6728422 | Doi | 10.1016/j.cell.2021.05.028 |
| Citation | Wong HS, et al. (2021) A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell 184(15):3981-3997.e22 |
| abstractText | 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. |
