Genetic resistance to herpesvirus‐induced lymphoma at the level of the target cell determined by the thymic microenvironment

Abstract

AbstractThe mechanisms responsible for non‐major‐histocompatibility‐complex (MHC)‐associated genetic resistance to Marek's disease (MD) were studied in resistant line 6 and susceptible line 7 chickens. Adoptive transfer of specific‐pathogen‐free (SPF) adult spleen cells from the susceptible line into irradiated 8‐day‐old resistant recipients significantly increased MD mortality following contact exposure to Marek's disease virus (MDV). No protective effect was observed following transfer of spleen cells from line 6 donors into susceptible line 7 recipients. Lymphocytes from the susceptible line 7 were shown by earlier experiments to have a higher capacity to adsorb the herpesvirus of turkeys (HVT). Fragments of thymic stroma from line 6 and line 7 were grafted onto the chorioallantoic membrane (CAM) of line 6 embryos. Following revascularization and repopulation of the grafts with lymphocytes of resistant host origin, the virus adsorption capacity of the non‐lymphoid stromal and lymphoid portions of the grafts was assayed in vitro by focus inhibition. While no difference in adsorption was observed between the line 6 and line 7 donor origin stromal cells, significantly more virus was adsorbed by the repopulating line 6 lymphoid cells harvested from the susceptible line 7 grafts than by line 6 lymphocytes from syngeneic line 6 grafts. The genotype of the thymic microenvironment was, therefore, found to be a determining factor in the expression of the high virus‐binding phenotype. Virus neutralizing monoclonal antibodies against HVT were prepared and used in the new in vitro antibody‐directed rosetting assay (ADRA) to determine the frequency of virus‐binding cells in the lymphoid organs of these two lines. Virus‐binding leukocytes were more frequent in the line 7 susceptible birds. In a time‐course study, following reconstitution of irradiated, third‐party, histocompatible recipients with SPF line 7 spleen cells, a sharp increase in MDV‐infectious centres was observed in peripheral blood at day 17 post exposure. A decrease in infectious centres was observed, however, at the same time point in recipients of line 6 spleen cells. The explanation for the difference in MD mortality seen in line 6 and line 7 is, thus, complex and may reflect separate resistance mechanisms which operate at more than one level. First, resistance is manifested at the level of a direct interaction between MDV and its target T lymphocyte with the thymic microenvironment playing a key role in the event. Second, and later during the course of infection, genetic variation in the capacity for immune surveillance against MDV‐infected and/or transformed cells may come into play. Whether these two properties segregate independently or not has yet to be determined.