The effect of aging on the immune response against E55+ murine leukemia retrovirus infection
Authors:   , Elrefaei Mohamed M. , Blank Kenneth J , Murasko Donna 
Published: July 2024

Aging is associated with increased incidence of virus infections. Although this has been attributed to age-related alterations in both T-cell mediated and humoral immunity, few studies have examined directly the relationship between decreased immune responsiveness and diminished control of virus infections in the aged. Further, the age-associated decrease in immune function is also associated with significant alterations in cytokine production. However, the effect of aging on cytokine production during a virus infection has not been directly examined. E55+ murine leukemia retrovirus (E55+MuLV) infection of young and aged C57BL/6 (B6) mice was used to investigate the relationship between increased incidences of infection and decreased immune responsiveness of elderly individuals. Young mice decreased E55+MuLV burden to below detectable levels by 8 weeks post infection (pi). In contrast, virus burden in aged mice did not reach undetectable levels until 20 weeks pi. A significant T cell proliferative response to E55+MuLV was detected from 2 to 12 weeks pi in young mice, but was never observed in aged mice. Both age groups demonstrated significant E55+MuLV-specific T cell mediated cytotoxic responses at 3 and 4 weeks pi and virus neutralizing antibody titers at 2, 4, 8 and 12 weeks pi. In both cases, responses were consistently higher in young mice (p < 0.04 and p < 0.02, respectively). These results suggest that the observed difference between young and aged mice in E55+MuLV clearance is associated with, and possibly due to, age-related alterations in both T and B cell responses to the virus. E55+MuLV infection of young and aged B6 mice was also used to investigate the effect of aging on cytokine production during virus infection. While it has been postulated that aging is associated with an increase in Type 2 cytokines and a decrease in Type 1 cytokines, our results showed that aged mice produced significantly lower levels of both Type 1 (IL-2 and IFN-[gamma]) and Type 2 (IL-10) cytokines compared to young mice (p < 0.05) at 2 and 4 weeks pi following virus-specific stimulation of spleen cells in vitro. Lower IL-2 and IFN-[gamma] levels were also associated with a significant reduction in the number of cells producing IL-2 and IFN-[gamma] (p < 0.02). IL-2 was produced by CD4+ T cells and IL-10 by B cells in both age groups. In contrast, IFN-[gamma] was produced mainly by CD4+ T cells at 2 weeks pi and by both CD4+ and CD8+ T cells at 4 weeks pi in young mice, while CD8+ T cells were the main source of IFN-[gamma] in aged mice at both times. These results demonstrate that the observed delay in virus clearance by aged mice is associated with an age-related decrease in both Type 1 and Type 2 cytokines as well as a shift in the primary source of at least one cytokine. In summary, our results demonstrate that the observed age-related differences in the proliferative, cytotoxic, and humoral responses against E55+MuLV between young and aged mice is associated with, and possibly due to, age-related alterations in both Type 1 and Type 2 cytokines.