Naive CD4+ T lymphocytes circulate through lymphoid organs to interact with endogenous antigens and upregulate their function.

Naive T lymphocytes recirculate through the lymph-vascular system and enter and exit lymphoid organs. Using mice expressing the photoconvertible fluorescence protein Kaede, we demonstrated that naive T cells seek to interact with endogenous Ags after migrating to the lymphoid organs. The interaction with endogenous Ags transiently induces CD69 expression on T cells, which prolongs retention in the lymphoid organs. Cells that fail to express CD69 or lose CD69 expression migrate to other lymphoid organs. Functionally, CD69(+)-naive CD4(+) T cells exhibit faster and greater cytokine production than do CD69(-) naive CD4(+) T cells. These results indicate that CD4(+) T cells continuously migrate to interact with endogenous Ags, and such an interaction plays an important role in the Ag reactivity of naive CD4(+) T cells.