Avidity and activation of TAA-specific T cells. (A) High-avidity CD8⁺ T cells that recognize target cells expressing endogenous levels of antigen are directed against non-self epitopes such as viral antigens or neo-antigens. Autoreactive T cells bearing TCRs that strongly react with self-peptides are deleted in the thymus (negative selection) or in the periphery. (B) Low-avidity self-reacting T cells can enter the periphery and need high ligand density to become activated. (C) However, intermediate-avidity T cells recognizing self-restricted TAAs can bypass negative selection in the thymus and mediate tumor cell lysis that depends on increased antigen expression, compared with non-malignant cells, or be promoted by inflammation, enhanced costimulation, or presentation by activated APCs. IFN, interferon; IL, interleukin; MHC, major histocompatibility complex.