Reactivation of latent herpesviruses is a particular problem in immunocompromised individuals such as AIDS patients who lack effective CD4 T helper cell function. Infection of mice with murine gammaherpesvirus-68 (MHV-68), which is closely related to the human pathogens Epstein Barr virus and Kaposi's sarcoma associated herpesvirus, provides a useful small animal model for studying the immune response to gamma herpesviruses and for testing the ability of potential immunotherapeutic agents to control viral reactivation. CD4 T cell deficient mice can clear an initial challenge with MHV-68, but fail to control latent virus, which later reactivates in the lungs. Using this mouse model of opportunistic infection, we showed that agonistic antibodies to CD40 could substitute for CD4 T cell function in preventing the reactivation of MHV-68 in CD4 T cell deficient mice. Our data also showed that CD8+ T cells were required for this effect. However, no difference in the number or cytolytic activity of CD8 cells was detected. In the linked application, experiments in Aim 1 were directed at determining whether anti-CD40 antibody treatment induced a direct change in the function of the CD8 T cells or acted at another essential step in the control of viral reactivation, without affecting CD8 T cell function. We have now obtained new data from adoptive transfer experiments, which show that anti-CD40 treatment induces a direct change in CD8 T cell function, enabling the control of viral reactivation. Hence we now have the justification to carry out more extensive studies to determine exactly how the CD8 T cells differ in anti-CD40 and control antibody-treated CD4 T cell-deficient mice during MHV-68 infection. In the current R21 application, we propose use gene microarrays to determine how gene expression differs in these functional and non-functional CD8 T cells. These studies are consistent with the exploratory nature of the R21 mechanism of support and the application of microarray technology is specifically cited in the Program announcement. We anticipate that the analyses will reveal differences in the expression of key regulatory or effector molecules. This will give us an insight into how CD8 T cell function is altered by the anti-CD40 antibody treatment or CD4 T cell help (mediated by CD40L) and what characteristics define a functional CD8 T cell. These studies will both extend and complement studies in the linked R01. The data are likely to lead to a new understanding of how CD8 T cells function in the control of persistent viral infections and mechanisms of CD8 T cell activation.
| Dias, Peter; Giannoni, Francesca; Lee, Lian Ni et al. (2010) CD4 T-cell help programs a change in CD8 T-cell function enabling effective long-term control of murine gammaherpesvirus 68: role of PD-1-PD-L1 interactions. J Virol 84:8241-9 |
