A method of generating a genetically modified non-human animal comprising: replacing at an endogenous non-human MHC II locus a nucleotide sequence(s) encoding a non-human MHC II complex with a nucleotide sequence(s) encoding a chimeric human/non-human MHC II complex comprising (i) chimeric human/non-human MHC II α polypeptide having human MHC II α1 and α2 domains of a human MHC II α polypeptide and (ii) chimeric human/non-human MHC β polypeptide having human MHC II β1 and β2 domains of a human MHC II polypeptide to generate a first embryonic stem cell, wherein the non-human portion of the chimeric MHC II α polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC II α polypeptide and wherein the non-human portion of the chimeric MHC II β polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC II β polypeptide, wherein the first ES cell comprises a nucleotide sequence encoding chimeric human/non-human MHC I polypeptide; or replacing at an endogenous non-human MHC I locus a nucleotide sequence encoding a non-human MHC I polypeptide with a nucleotide sequence encoding a chimeric human/non-human MHC I polypeptide comprising human α1, α2, and α3 domains of a human MHC I polypeptide to generate a second ES cell, wherein the non-human portion of the chimeric MHC I polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC I polypeptide, wherein the second ES cell comprises a nucleotide sequence(s) encoding chimeric human/non-human MHC II complex; and generating a non-human animal from the first or second embryonic stem cell. replacing at an endogenous non-human MHC II locus a nucleotide sequence(s) encoding a non-human MHC II complex with a nucleotide sequence(s) encoding a chimeric human/non-human MHC II complex comprising (i) chimeric human/non-human MHC II α polypeptide having human MHC II α1 and α2 domains of a human MHC II α polypeptide and (ii) chimeric human/non-human MHC β polypeptide having human MHC II β1 and β2 domains of a human MHC II polypeptide to generate a first embryonic stem cell, wherein the non-human portion of the chimeric MHC II α polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC II α polypeptide and wherein the non-human portion of the chimeric MHC II β polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC II β polypeptide, wherein the first ES cell comprises a nucleotide sequence encoding chimeric human/non-human MHC I polypeptide; or replacing at an endogenous non-human MHC I locus a nucleotide sequence encoding a non-human MHC I polypeptide with a nucleotide sequence encoding a chimeric human/non-human MHC I polypeptide comprising human α1, α2, and α3 domains of a human MHC I polypeptide to generate a second ES cell, wherein the non-human portion of the chimeric MHC I polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC I polypeptide, wherein the second ES cell comprises a nucleotide sequence(s) encoding chimeric human/non-human MHC II complex; and generating a non-human animal from the first or second embryonic stem cell.