Peripheral deletion of CD8 T cells requires p38 MAPK in cross-presenting dendritic cells

Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self-reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4⁺Foxp3+ T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion. In this study, we used several different models of CD8 T cell deletion to investigate the contribution of MAPK activation. Using chemical inhibitors, we established that inhibition of p38, but not ERK or JNK, rescue T cells from undergoing peripheral deletion both in vitro and in vivo. Using T cell-specific murine lines genetically altered in expression of p38a, and mice in which p38a was deleted only in CD11c-expressing cells, we surprisingly found that CD8 T cell-intrinsic p38a activation was not responsible for increased survival, but rather that inhibition of p38a in the Ag-presenting dendritic cells prevented CD8 T cell deletion.