Human CD4-major histocompatibility complex class II (DQw6) transgenic mice in an endogenous CD4/CD8-deficient background: reconstitution of phenotype and human-restricted function.
To reconstitute the human immune system in mice, transgenic mice expressing human CD4 and human major histocompatibility complex (MHC) class II (DQw6) molecules in an endogenous CD4- and CD8-deficient background (mCD4/8-/-), after homologous recombination, have been generated. We report that expression of human CD4 molecule in mCD4/8-/- mice rescues thymocyte development and completely restores the T cell compartment in peripheral lymphoid organs. Upon vesicular stomatitis virus (VSV) challenge, the reconstituted mature T cell population effectively provide T help to B cells in immunoglobulin class switching from IgM to specific IgG-neutralizing antibodies. Human CD4+DQw6+ double transgenic mice are tolerant to DQw6 and the DQw6 molecule functions in antigen presentation, effectively generating a human MHC class II-restricted T cell response to streptococcal M6C2 peptide. These data show that both the hCD4 and DQw6 molecules are functional in mCD4/8-/- mice, fully and stably reconstituting this limb of the human immune system in mice. This animal model provides a powerful in vivo tool to dissect the human CD4-human class II MHC interaction, especially its role in human autoimmune diseases, superantigen-mediated diseases, and acquired immunodeficiency syndrome (AIDS).
Yeung
R S
RS
Department of Immunology, Ontario Cancer Institute, University of Toronto, Canada.
Penninger
J M
JM
Kündig
T M
TM
Law
Y
Y
Yamamoto
K
K
Kamikawaji
N
N
Burkly
L
L
Sasazuki
T
T
Flavell
R
R
Ohashi
P S
PS
Mak
T W
TW
D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016827:CD8 Antigens / Q000032:analysis*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000502:physiology*; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013601:T-Lymphocytes / Q000502:physiology
D015704:CD4 Antigens; D016827:CD8 Antigens; D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen