Duration of antigen availability influences the expansion and memory differentiation of T cells1

The initial engagement of the T cell receptor (TCR) through interaction with cognate peptide-MHC is a requisite for T cell activation and confers antigen specificity. While this is a key event in T cell activation, the duration of these interactions may affect the proliferative capacity and differentiation of the activated cells. Here, we developed a system to evaluate the temporal requirements for antigenic stimulation during an immune response, in vivo. Using antibodies that target specific antigens in the context of MHC, we were able to manipulate the duration of antigen availability to both CD4 and CD8 T cells during an active infection. During the primary immune response, the magnitude of the CD4 and CD8 T cell response was dependent on the duration of antigen availability. Both CD4 and CD8 T cells required sustained antigenic stimulation for maximal expansion. Memory cell differentiation was also dependent on the duration of antigen exposure, albeit to a lesser extent. However, memory development did not correlate with the magnitude of the primary response, suggesting that the requirements for continued expansion of T cells and memory differentiation are distinct. Finally, a shortened period of antigen exposure was sufficient to achieve optimal expansion of both CD4 and CD8 T cells during a recall response. It was also revealed that limiting exposure to antigen late during the response may enhance the CD4 T cell memory pool. Collectively, these data indicated that antigen remains a critical component of the T cell response after the initial APC-T cell interaction.