The absence of a need for co-signaling through CD28 for these BiTEs might also be explained by the observation that among all T cell subtypes, CD8+ effector memory cells CD45RO+ (TEM) and CD8+ effector memory CD45RA+ (TEMRA) contribute the most to BiTE activity, whereas naïve T cells do not contribute at all to the killing efficiency.50 It is believed that memory T cells do not require CD28 costimulation for expansion during secondary responses, which could explain the efficiency of BiTEs. However, this dogma has recently been challenged.5