PD-1 is a checkpoint inhibitor widely studied for cancer immunotherapy settings. A high proportion of cancer patients do not respond or acquire resistance to PD-1 immunotherapy. The reasons behind this lack of effectiveness are still being studied. Importantly, PD-1 is also involved in maintaining peripheral tolerance and preventing autoimmunity. A systemic approach for PD-1 blockade might affect T cell subsets in different ways that may be detrimental for the therapy and patients. Here we aimed to study the role of PD-1 in CD4+ T cells in the cross-regulation of CD8+ T cell populations in a peripheral tolerance setting. For this, we used CRISPR/Cas9 technology to knock out PD-1 in chromogranin-A islet antigen specific CD4+ T cells (BDC2.5 cells) to investigate the role of PD-1 in cross-tolerance of autoreactive CD8+ T cells in a type 1 diabetes context. We co-transferred PD-1KO BDC2.5 CD4+ T cells together with IGRP-specific CD8+ T cells into NOD mice and used flow cytometry to monitor their proliferation and phenotype four days later. We found that CD4+ T cells that lacked PD-1 were unable to control the proliferation of CD8+ T cells in the pancreatic lymph node (pLN) where both the chromogranin-A and IGRP antigens are presented. In the absence of PD-1 on the CD4+ T cells, the CD8+ IGRP-specific T cells gained an effector memory phenotype. Within the antigen-presenting cell compartment, CD11b+XCR1- conventional dendritic cells (cDCs) located in the pLN had an immature profile only in the presence of BDC2.5 CTRLKO CD4+ T cells, with low MHCII MFI and low surface expression of CD40 and CD86. Additionally, mice co-transferred with PD-1KO BDC2.5 CD4+ T cells and IGRP-specific CD8+ T cells had accelerated diabetes compared to mice that received CTRLKOCD4+ T cells and IGRP-specific CD8+ T cells. Together this shows that PD-1+CD4+ T cells are important to suppress effector memory CD8+ T cells, via modulation of CD11b+XCR1+ cDCs. This evidence supports the idea that blockade of PD-1 could promote imbalances in peripheral tolerance mechanisms. Even though PD-1 is a key target for cancer immunotherapies, we revealed important autoimmune mechanisms that could be triggered as side effects of checkpoint inhibition.