Figure 2.

Overview of CAR-T development from TCR. (Left) T cell receptor (TCR) is a natural complex formed by six chains: two variable chains (α and β) that bind specific antigens after MHC-II presentation and four constant chains (γ, 𝛿, ϵ and 𝜁) that activate the T cell after 1^st signal. Second co-stimulation signal, normally from CD28, is necessary for maintaining activation. (Right) On the other hand, chimeric antigen receptor (CAR) is an artificial receptor with three domains: one that recognizes antigens independently of the HLA complex (scFv, single chain variable fragment) and is linked by a transmembrane domain to the activation domain CD3𝜁 to activate the T cell in the first generation of CAR. Second and third generation includes one and two more costimulatory domains (CM1 and CM2), respectively. Most frequent CM encloses CD28 or 4-1BB. Forth CAR generation also express bioactive molecules such as cytokines or Bi-specific T-cell engagers (BiTEs). General levels of activation or potency are represented with a star symbol: yellow star indicates the potential to modulate microenvironment (figure created with www.biorender.com).