anergy

Anergy is a state of functional unresponsiveness in immune cells, most commonly T lymphocytes, to an antigen they can recognize. In T cells, anergy typically occurs when the T cell receptor engages its antigen without the accompanying co-stimulatory signals necessary for full activation, such as CD28 binding to B7 on antigen-presenting cells. The result is a loss of proliferative capacity and impaired cytokine production, particularly interleukin-2, upon subsequent encounters with the same antigen.

Mechanistically, several processes contribute to anergic T cells. There is insufficient activation of growth and survival pathways, altered calcium signaling, and the induction of negative regulatory molecules such as Cbl-b, GRAIL, and others that dampen TCR signaling. Inhibitory receptors, including PD-1 and CTLA-4, may be upregulated, further reducing responsiveness. Anergy is a peripheral tolerance mechanism designed to prevent autoimmunity by converting potentially self-reactive T cells into a non-responsive state. Regulatory T cells and immunosuppressive cytokines can also promote or maintain anergic states.

B cell anergy is another related concept, describing mature B cells that remain unresponsive to self-antigen and require helper signals to become activated, contributing to self-tolerance.

Clinical relevance includes roles in preventing autoimmunity through peripheral tolerance, and in tumor immunology where tumor-induced anergy helps evade immune detection. Therapeutically, reversing anergy with immune checkpoint inhibitors or other agents is a strategy in cancer treatment, while promoting anergy can be a goal in transplant tolerance or autoimmune control. The term anergy originated in the 1960s to describe this unresponsive state after antigen exposure without adequate costimulation.