Role of co-stimulation in CD8+ T cell activation

The two-signal model states that activation of naive T cells requires a signal I stimulus through the TCR and a cc-stimulatory signal 2, By contrast, signal 1 alone is sufficient for pre-activated T cells, Recently, however, it has been shown that under certain conditions T cells can bypass the requirement for co-stimulation. For example, CD28-deficient mice, when immunized with lymphocytic choriomeningitis virus, mount a Vigorous cytotoxic T lymphocyte response and clear the virus, As a continuous effort to unravel the mechanisms of T cell activation, we previously reported activation of hybridoma T cells by recombinant single-chain MHC molecules in the absence of antigen-presenting cells. In such reconstitution experiments, since the signals delivered to the T cells are well controlled, the contribution of any known or unknown signals can be ruled out, In the present study, we analyzed the requirements for activation of naive T cells by using splenocytes from TCR transgenic mice as a source of responding cells, We observed that naive CD8(+) T cells are fully activated by signal 1 alone, but that cc-stimulation lowers their activation threshold. Previously activated T cells are fully responsive, even when the first stimulation was performed in the absence of co-stimulation. They display a low activation threshold and are insensitive to co-stimulation. The physiological relevance of this finding and its consequences for immunotherapy as well as for our understanding of self-tolerance are discussed.