Cytotoxic T lymphocytes (CTLs) that cause type 1 diabetes are activated in the draining lymph nodes and become concentrated as fully active CTLs in inflamed pancreatic islets. We have shown maturation from activated CD8+ T cell to fully armed effector CTL occurs within the islet, not in the lymph nodes. Autoreactive CTLs found within islets of diabetes prone NOD mice display increased expression of the cytotoxicity markers GzmB, IFNγ and CD107a and this correlated with enhanced cytotoxic function. The islet is also the site where CTLs acquire an effector memory phenotype. Interferons and common γ chain cytokines such as IL-7, IL-21 and IL-15, can provide additional signals to generate fully active CTLs and drive effector memory differentiation and these are present within the inflamed islet. We propose that CTLs respond to cytokines in the islet and this supports CTL maturation and differentiation, enhancing CTL ability to kill beta cells. We have developed a panel of transgenic, knockout and reporter mice to assess this response and to identify which cytokines are responsible. Beta cell antigen specific CD8+ T cells adoptively transferred into NOD mice showed an increase in Jak-STAT pathway reporter expression as the cells divided in islets, indicating cytokine exposure. Eliminating type I IFN signaling had no effect on reporter or GzmB expression. In contrast, eliminating IL-21 responsiveness prevented the increase in GzmB expression in islet CTLs. This indicates that CTLs within islets respond to IL-21 and this increases markers associated with cytotoxicity. Our data clarify mechanisms of diabetogenic CTL maturation within the islet and suggest a role for neutralization of IL-21 in beta-cell protection from cytotoxicity.