What signals does a naive T cell need to become fully activated?

Why

Requiring two signals is a safety mechanism. Self peptides are presented everywhere, but costimulatory B7 molecules appear mainly on antigen-presenting cells that have sensed infection or damage. A T cell that sees its peptide without costimulation tends to become unresponsive, a state called anergy, instead of attacking.

Chen and Flies describe how the discovery of CD28 established this two-signal model, and how it has since grown into a network of costimulatory and coinhibitory receptors. CTLA-4 competes with CD28 for B7 and damps activation, while PD-1 restrains T cells in tissues. Cytokines such as IL-12 or IL-4 present during priming push CD4 cells toward different helper programs.

The model explains several drug classes. Abatacept blocks costimulation to treat autoimmunity. Checkpoint antibodies against CTLA-4 or PD-1 remove brakes to treat cancer.

It also explains a failure. The CD28 superagonist TGN1412 gave healthy volunteers a severe cytokine storm in 2006, because bypassing normal control activated T cells broadly. In lab assays, plate-bound anti-CD3 alone gives weaker activation than anti-CD3 plus anti-CD28 for the same reason.