There are many anti-tumor contributions of the immune system, the direct cytolytic effect of the adaptive immune system has been attributed to CD8 T cells. However emerging evidence suggests that CD4 T cells are also capable of cytolytic mechanisms in addition to their “helper” functions for effector CD8 T cells, B cells, and antigen presenting cells. We previously described the Immuno-STAT (IST) biologics platform, a class of antigen-selective T cell modulators composed of a covalent peptide-major histocompatibility complex unit and a co-modulatory domain designed to deliver specific functional signals. CD8-targeting ISTs, based on class I MHC molecules, selectively expand and activate antigen-specific T cell populations, while leaving the remainder of the repertoire untouched, and are currently in clinical trials for multiple oncology indications. Here we describe the production of CD4-targeting ISTs, based on class II MHC molecules, and demonstrate that an HLA-DR1 MHC II IST incorporating the immunodominant HA(306–318) epitope can drive antigen-specific expansion of CD4 T cells. Importantly, this approach establishes the foundation for the generation of MHC class II ISTs that engage CD4 T cells specific to tumor antigens.