costimulation

Costimulation refers to the additional signals required by many immune cells, especially T lymphocytes, to achieve full activation. In its absence, engagement of the T cell receptor with peptide-MHC may produce only a partial response or lead to anergy or tolerance. Costimulatory interactions are typically delivered by antigen-presenting cells and other accessory cells through receptor-ligand pairs.

The prototypical T cell costimulation is the engagement of CD28 on T cells with B7-1 (CD80) or B7-2 (CD86) on professional antigen-presenting cells. This signal enhances IL-2 production, proliferation, and survival. Several additional costimulatory receptors contribute, including ICOS, OX40, and 4-1BB, while CTLA-4 and PD-1 deliver inhibitory signals to restrain activation. The net outcome depends on the balance of stimulatory and inhibitory inputs, the maturation state of the APC, and the cytokine milieu.

Costimulation also supports B cell responses through CD40-CD40L interactions, promoting isotype switching, germinal center formation, and antibody production. Other accessory signals influence NK cells and other lymphocytes, reflecting a broader role in shaping adaptive immunity.

Clinical relevance: Therapeutic strategies target costimulation to modulate immunity. Blocking CD28-B7 interactions with CTLA-4–Ig or anti-B7 antibodies can prevent transplant rejection or treat autoimmune disease, whereas checkpoint inhibitors that block PD-1/PD-L1 or CTLA-4 enhance anti-tumor immunity. Abnormal costimulation can contribute to autoimmunity or immunodeficiency.

In summary, costimulation is a key layer of adaptive immune regulation that ensures activation occurs in appropriate immunological contexts and coordinates responses across T cells, B cells, and other leukocytes.