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 mai ntenance of immune memory that protects against reinfection are mediated pr imarily through the anti-MV T cell response, as judged by observations of c hildren with defects in antibody formation but competency in making T cells . Further, the failure of T cell responses in those infected with MV most o ften leads to overwhelming infection. To better define and manipulate the e lements involved in human T cell responses to MV, we analyzed the generatio n of HLA-restricted cytotoxic T lymphocytes (CTL) in a small animal model. Transgenic mice expressing the human class I MHC antigen HLA-B27 in conjunc tion with human CD8 molecules produced vigorous HLA-restricted CTL response s to MV antigens, paralleling those in MV infection of humans. In addition, such humanized mice generated human CD8 coreceptor-dependent HLA-B27-restr icted CTL with the same specificity for recognition of MV fusion (F) peptid e RRYPDAVYL as reported for humans during natural MV infection. Neither mur ine beta(2)-microglobulin nor murine CD8 substituted adequately as corecept ors 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 th e molecular mechanism of MV-induced immunosuppression. (C) 2000 Academic Pr ess.