Positive selection of CD4⁺ t cells is induced in vivo by agonist and inhibited by antagonist peptides

The nature of peptides that positively select T cells in the thymus remains poorly defined. Here we report an in vivo model to study the mechanisms of positive selection of CD4⁺ T cells. We have restored positive selection of TCR transgenic CD4⁺ thymocytes, arrested at the CD4⁺CD8⁺ stage, due to the lack of the endogenously selecting peptide(s), in mice deficient for H2-M and invariant chain. A single injection of soluble agonist peptide(s) initiated positive selection of CD4⁺ transgenic T cells that lasted for up to 14 days. Positively selected CD4⁺ T cells repopulated peripheral lymphoid organs and could respond to the antigenic peptide. Furthermore, coinjection of the antagonist peptide significantly inhibited agonist-driven positive selection. Hence, contrary to the prevailing view, positive selection of CD4⁺ thymocytes can be induced in vivo by agonist peptides and may be a result of accumulation of signals from TCR engaged by different peptides bound to major histocompatibility complex class II molecules. We have also identified a candidate natural agonist peptide that induces positive selection of CD4⁺ TCR transgenic thymocytes.