Atlantic cod and codfish (Gadiformes) lack major histocompatibility complex (MHC) class II and CD4+ T cells, components of the immune system that are central to autoimmune diseases and to fight bacterial infections. In mammalians, the MHC class II molecules are expressed in cells of the immune system like B cells, monocytes, macrophages and dendritic cells. Here, the MHC class II molecules control the specificity of the immune response by presenting fragments from proteins that are degraded in the endosomal pathway to CD4+ T cells. In the absence of MHC class II, such as in bare lymphocyte syndrome type II patients and in MHC class II-deficient mice, the immune system fails to respond properly to infections, ultimately leading to life-threatening conditions. It remains a mystery then, how codfish lacking the MHC class II pathway, can efficiently fight diseases. By studying Atlantic cod MHC I in cod cell lines and primary cells, we aim to search for and determine the function of new players and pathways that might compensate for the absence of the MHC class II pathway.