On T cell development, T cell signals, T cell specificity and sensitivity, and the autoimmunity facilitated by lymphopenia.

We propose a framework to explain how T cells achieve specificity and sensitivity, how the affinity of the TcR peptide/MHC interaction controls positive and negative thymic selection and mature T cell survival, and whether antigen-dependent activation and inactivation takes place. Two distinct types of signalling can lead to mature T cell multiplication. One requires the TcR to recognize with a certain affinity an antigen-derived peptide, an agonist peptide, bound to an MHC molecule. The other, the tonic signal, leads to naïve T cell survival and modest proliferation if the T cell successfully competes for endogenous, self-peptide/MHC ligands, involving lower affinity TCR/ligand interactions. Many suggest lymphopenia contributes to autoimmunity by increasing the strength of TcR-tonic signalling, and so activation of anti-self T cells. We suggest T cell activation requires antigen-mediated cooperation between T cells. Increased tonic signalling under lymphopenic conditions facilitates T cell proliferation and so antigen-dependent cooperation and activation of anti-self T cells.