coinhibitory

Coinhibitory is an adjective used in biology and medicine to describe signals or receptors that inhibit cellular activation. In immunology, coinhibitory signals refer to pathways that dampen immune responses, acting to maintain self-tolerance and prevent autoimmunity. These signals contrast with costimulatory signals that boost activation; together they shape the amplitude and duration of immune responses. Dysregulation of coinhibitory pathways can contribute to immune exhaustion in chronic infection and to immune evasion by cancers.

Key coinhibitory receptors include PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT, expressed on T cells and, in some cases, other leukocytes. Their ligands (such as PD-L1, PD-L2, and B7 family ligands) are expressed on antigen-presenting cells and on many tumor cells. Engagement of these receptors inhibits TCR signaling through phosphatases like SHP-2, leading to reduced proliferation, cytokine production, and cytotoxic activity. BTLA and VISTA are additional examples. These checkpoints regulate tolerance at multiple stages including priming in lymphoid tissues and effector responses in peripheral tissues.

Clinically, blockade of coinhibitory pathways with monoclonal antibodies—checkpoint inhibitors—has transformed cancer therapy by reinvigorating anti-tumor T cells. Anti-PD-1/PD-L1 and anti-CTLA-4 therapies are approved for several cancers; combination regimens can enhance responses but increase immune-related adverse events, autoimmune-like effects caused by increased immune activity.

Beyond cancer, coinhibitory signaling participates in preventing autoimmunity and limiting immunopathology in infections; ongoing research seeks to understand mechanisms of resistance and optimal use of combination therapies.

In neuroscience, the term coinhibitory can describe neural circuits where inhibitory inputs cooperate to suppress activity, though it is less standardized and not as widely used as in immunology.