Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4(+) T cell development

Efficient positive selection of a broad repertoire of T cells is dependent on the presentation of a diverse array of endogenous peptides on MHC molecu les in the thymus. It is unclear, however, whether the development of indiv idual TCR specificities is influenced by the abundance of their selecting l igands, To examine this, we analyzed positive selection in a transgenic mou se carrying a TCR specific for the human CLIP:I-A(b) class II complex. We f ound that these mice exhibit significantly reduced CD4(+) T cell developmen t compared with two other transgenic mice carrying TCRs selected on I-A(b). Moreover, many of the selected cells in these mice express endogenous and transgenic receptors as a consequence of dual TCR alpha expression. Dramati c enhancement of the selection efficiency is observed, however, when fewer transgenic cells populate the thymus in mixed bone marrow chimeras. These r esults suggest that positive selection is limited by the availability of se lecting peptides in the thymus, This becomes apparent when large numbers of thymocytes compete for such peptides in TCR transgenic animals. Under such conditions, thymocytes appear to undergo further TCR alpha gene rearrangem ent to produce a receptor that may be selected more efficiently by other th ymic self-peptides.