Transgenic mice expressing human HLA and CD8 molecules generate HLA-restricted measles virus cytotoxic T lymphocytes of the same specificity as humans with natural measles virus infection.
Control of primary measles virus (MV) infection in humans and continued maintenance of immune memory that protects against reinfection are mediated primarily through the anti-MV T cell response, as judged by observations of children with defects in antibody formation but competency in making T cells. Further, the failure of T cell responses in those infected with MV most often leads to overwhelming infection. To better define and manipulate the elements involved in human T cell responses to MV, we analyzed the generation of HLA-restricted cytotoxic T lymphocytes (CTL) in a small animal model. Transgenic mice expressing the human class I MHC antigen HLA-B27 in conjunction with human CD8 molecules produced vigorous HLA-restricted CTL responses to MV antigens, paralleling those in MV infection of humans. In addition, such humanized mice generated human CD8 coreceptor-dependent HLA-B27-restricted CTL with the same specificity for recognition of MV fusion (F) peptide RRYPDAVYL as reported for humans during natural MV infection. Neither murine beta(2)-microglobulin nor murine CD8 substituted adequately as coreceptors for the HLA-B27 heavy chain. By contrast, HLA-A2.1-restricted responses to measles could be generated in the absence of expression of human beta(2)-microglobulin or CD8(+) molecules in HLA-A2.1/K(b) transgenic mice. Thus a small animal model is now available for studying strategies for optimizing human CD8(+) T cell responses and for testing vaccines. This model offers the potential, when combined with the newly reported CD46 transgenic mouse model in which MV replicates in cells of the immune system, for uncoding the molecular mechanism of MV-induced immunosuppression.
Tishon
A
A
Division of Virology, The Scripps Research Institute, La Jolla, California 92037, USA.
LaFace
D M
DM
Lewicki
H
H
van Binnendijk
R S
RS
Osterhaus
A
A
Oldstone
M B
MB
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism*; D004195:Disease Models, Animal; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism; D008457:Measles / Q000276:immunology*; D008459:Measles virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D016827:CD8 Antigens; D015796:HLA-B27 Antigen; D007143:Immunoglobulin Heavy Chains