Antigen‐specific Treg impair CD8+ T‐cell priming by blocking early T‐cell expansion

Foxp3⁺ Treg are crucial for the maintenance of self‐tolerance and have been shown to control CD8⁺ T‐cell effector functions. In addition, Treg are thought to control the priming of CD8⁺ T cells, which recognize the same antigens as Treg. Taking advantage of our model of peripheral tolerance induction to influenza hemagglutinin (HA) after HA gene transfer, we found that HA‐specific Treg suppress antigen‐linked CTL responses through early blockade of CD8⁺ T‐cell expansion. Confronted with their cognate antigen, Treg expand more rapidly than CD8⁺ T cells and are highly suppressive only during the initial stages of immune priming. They nullify HA‐specific CD8⁺ T‐cell responses, local inflammatory responses and rejection of HA transduced cells. When HA gene transfer is performed with extensive tissue inflammation, HA‐specific Treg are less effective but still reduce the frequency of newly primed HA‐specific CD8⁺ T cells and the ensuing frequency of memory CD8⁺ T cells. Our results demonstrate that Treg control CTL priming in an antigen‐specific manner at the level of T‐cell expansion, highlighting how self‐reactive Treg could prevent the induction of autoimmune responses through selective blockade of autoreactive T‐cell proliferation.