A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.
Cell
; 184(15): 3981-3997.e22, 2021 07 22.
Article
en En
| MEDLINE
| ID: mdl-34157301
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
/
Linfocitos T Reguladores
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Retroalimentación Fisiológica
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Homeostasis
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Cell
Año:
2021
Tipo del documento:
Article