A genetically modified rodent, comprising a nucleotide sequence encoding a chimeric human/rodent CD4 polypeptide, a nucleotide sequence encoding a humanized MHC II α polypeptide, and a nucleotide sequence encoding a humanized MHC II β polypeptide, wherein the nucleotide sequence encoding a chimeric human/rodent CD4 polypeptide is present at an endogenous rodent CD4 co-receptor locus, and the nucleotide sequences encoding a humanized MHC II α polypeptide and a humanized MHC II β polypeptide are present at an endogenous rodent MHC II locus; wherein the rodent does not express a functional endogenous rodent CD4 co-receptor from its endogenous CD4 locus, wherein the rodent does not express a functional endogenous rodent MHC II α polypeptide from the endogenous MHC II locus, wherein the rodent does not express a functional endogenous rodent MHC II β polypeptide from the endogenous MHC II locus, wherein the chimeric human/rodent CD4 polypeptide comprises at least the MHC II binding domain of a human CD4 polypeptide and at least transmembrane and cytoplasmic domains of a rodent CD4 polypeptide, wherein the humanized MHC II α polypeptide comprises α1 and α2 domains of a human MHC II α polypeptide and transmembrane and cytoplasmic domains of a rodent MHC II α polypeptide, wherein the humanized MHC II β polypeptide comprises β1 and β2 domains of a human MHC II β polypeptide and transmembrane and cytoplasmic domains of a rodent MHC II β polypeptide, wherein the rodent expresses the chimeric human/rodent CD4 polypeptide and a humanized MHC II protein comprising the humanized MHC II α and humanized MHC II β polypeptides, and wherein the chimeric human/rodent CD4 polypeptide and the humanized MHC II protein interact. a nucleotide sequence encoding a chimeric human/rodent CD4 polypeptide, a nucleotide sequence encoding a humanized MHC II α polypeptide, and a nucleotide sequence encoding a humanized MHC II β polypeptide, wherein the nucleotide sequence encoding a chimeric human/rodent CD4 polypeptide is present at an endogenous rodent CD4 co-receptor locus, and the nucleotide sequences encoding a humanized MHC II α polypeptide and a humanized MHC II β polypeptide are present at an endogenous rodent MHC II locus; wherein the rodent does not express a functional endogenous rodent CD4 co-receptor from its endogenous CD4 locus, wherein the rodent does not express a functional endogenous rodent MHC II α polypeptide from the endogenous MHC II locus, wherein the rodent does not express a functional endogenous rodent MHC II β polypeptide from the endogenous MHC II locus, wherein the chimeric human/rodent CD4 polypeptide comprises at least the MHC II binding domain of a human CD4 polypeptide and at least transmembrane and cytoplasmic domains of a rodent CD4 polypeptide, wherein the humanized MHC II α polypeptide comprises α1 and α2 domains of a human MHC II α polypeptide and transmembrane and cytoplasmic domains of a rodent MHC II α polypeptide, wherein the humanized MHC II β polypeptide comprises β1 and β2 domains of a human MHC II β polypeptide and transmembrane and cytoplasmic domains of a rodent MHC II β polypeptide, wherein the rodent expresses the chimeric human/rodent CD4 polypeptide and a humanized MHC II protein comprising the humanized MHC II α and humanized MHC II β polypeptides, and wherein the chimeric human/rodent CD4 polypeptide and the humanized MHC II protein interact.