In vivo CD4(+) T cell tolerance induction versus priming is independent ofthe rate and number of cell divisions

In vitro studies have suggested that tolerance induction (i.e., anergy) is associated with an inability of T cells to proliferate vigorously upon Ag r ecognition. In vivo, the relationship between T cell proliferation and tole rance induction is less clear To clarify this issue, we have been studying a model system in which naive CD4(+) T cells specific for the model Ag hema gluttinin (HA) are adoptively transferred into different transgenic founder lines of mice expressing HA as a peripheral self-Ag. When transferred into two lines whose HA expression differs by at least 1000-fold, HA-specific T cells undergo multiple rounds of cell division before reaching a nonrespon sive (i.e., tolerant) state, While the proliferative response is more rapid in mice expressing higher levels of HA, the T cells become tolerant regard less of the level of peripheral HA expression, When the T cells encounter H A expressed as a viral Ag, they proliferate at a similar rate and undergo t he same number of divisions as with self-HA, but they do not become toleran t, These results indicate that a tolerizing stimulus can induce similar T c ell mitotic rates as a priming stimulus. Therefore, CD4(+) T cell tolerance induction in vivo is not the result of an insufficient proliferative respo nse elicited upon TCR engagement.