Viral escape of MHC-dependent immune recognition in a mouse/influenza model

Because the genes of the Major Histocompatibility Complex (MHC) function in immune recognition, it is generally believed that pathogen-driven selection accounts for the unprecedented diversity found at these loci. Two approaches were used for immunoselection of viral escape variants of MHC-dependent immune recognition in a mouse/influenza model. First, immunoselection for viral escape variants was attempted in the context of a monoclonal T-cell response using three different strains of T-cell receptor transgenic (TCR-tg) mice. Each strain recognized a single epitope of the hemagglutinin gene of influenza A/PR/8/34 as follows: (1) II VBH recognizes a class II epitope a.a. 110-119, (2) II STF recognizes a class II epitope a.a. 126-138 and (3) I STF recognizes a class I epitope a.a. 512-528. Second, immunoselection for viral escape variants was attempted in the context of a polyclonal T-cell response using C57BL/6 mice immunized with a vaccinia recombinant, containing the nucleoprotein gene of influenza A/PR/8/34, which has only one class I epitope (a.a. 365-380). These immunized mice and controls were then challenged with influenza A/PR/8/34. Prior to conducting these experiments, several preliminary studies were undertaken to better understand crucial aspects of the mouse/influenza model. The first study evaluated the potential of genetic immunization for favoring immunoselection of escape variants. The second evaluated different methods of immunization in {dollar}betasb2{dollar}-microglobulin deficient mice. The third study investigated the dynamics of influenza infection in class I TCR-tg mice. The data demonstrated that genetic immunization with an epitope specific construct is not efficient. In addition, routes of immunization that stimulate the mucosal immune system may protect immunocompromised mice such as {dollar}betasb2{dollar}-microglobulin deficient and TCR-tg mice from a lethal influenza challenge. Surprisingly, class I TCR-tg mice are more resistant to infection with wildtype influenza A/PR/8/34 than BALB/c controls. The results indicate that no escape variants of MHC-dependent immune recognition emerged in experiments that passaged virus through either class I or class II TCR-tg mice (monoclonal immune response) or nucleoprotein immunized C57BL/6 mice (polyclonal immune response). However, passaging through the class I TCR-tg mice did select for a more virulent strain of influenza A/PR/8/34.