Costimulaire

Costimulaire, in immunology, refers to molecular signals that provide the second activation signal required for certain immune cells, most notably T lymphocytes, to become fully activated. The activation of naive T cells generally depends on two signals: antigen recognition through the T cell receptor (signal 1) and a costimulatory signal (signal 2) delivered by interactions between receptors on T cells and ligands on antigen-presenting cells (APCs). Without costimulation, T cells may become anergic, die by apoptosis, or fail to divide, contributing to peripheral tolerance.

Mechanism and key players: The classic costimulatory interaction involves CD28 receptors on T cells engaging B7 molecules (CD80 and CD86) on APCs. Beyond CD28, other positive costimulators include ICOS-ICOSL, OX40-OX40L, and the TNF receptor family members such as 4-1BB (CD137) and CD40-CD40L. In addition to activation-promoting pathways, there are inhibitory costimulatory signals mediated by receptors like CTLA-4 and PD-1 that dampen T cell responses when engaged by their ligands. The balance of these signals shapes T cell expansion, cytokine production, and differentiation into effector or memory cells.

Clinical relevance: Modulating costimulatory pathways has therapeutic implications. Blockade of costimulation (for example, abatacept, a CTLA-4–Ig fusion protein) can reduce inappropriate T cell activation in autoimmune diseases. Conversely, strategies that provide or amplify costimulatory signaling, including agonist antibodies targeting OX40 or 4-1BB, aim to boost anti-tumor immunity. Immune checkpoint inhibitors that release inhibitory costimulation, such as anti-CTLA-4 and anti-PD-1/PD-L1 therapies, have transformed cancer treatment.

Summary: Costimulaire signals are central regulators of T cell activation, tolerance, and effector function, and are a major focus of contemporary immunology and immunotherapy.