Positive selection of CD4+ T cells by TCR-specific antibodies requires low valency TCR cross-linking: implications for repertoire selection in the thymus

The developmental fate of immature CD4⁺ 8⁺ thymocytes is determined by intrathymic signals transduced by surface TCR complexes. In particular, TCR signals are required for immature CD4⁺ 8⁺ thymocytes to further differentiate into CD4⁺ 8⁻ or CD4⁻ 8⁺ T cells, a process referred to as positive selection. It is generally thought that positive selection results from low affinity TCR interactions with self antigens which engage the relatively few surface TCR complexes that are on immature CD4⁺ 8⁺ thymocytes. However, we now demonstrate with TCR-specific antibodies that positive selection of CD4⁺ T cells requires low valency cross-linking of surface TCR complexes on immature thymocytes. That is, positive selection signals are only generated within a narrow range of TCR cross-linking: cross-linking either too few or too many surface TCR complexes fails to signal positive selection. We interpret these results as indicating that positive selection of CD4⁺ T cells is not signaled by low affinity TCR interactions per se, but rather can be signaled by any combination of TCR affinity and ligand density that induces low valency TCR cross-linking on immature thymocytes.