CD8+ T Cells Prevent Lethality from Neonatal Murine Roseolovirus Infection

Abstract

A recently described mouse homolog of the human roseoloviruses, murine roseolovirus (MRV), causes loss of peripheral and thymic CD4+ cells during neonatal infection of BALB/c mice. Despite significant disruptions to the normal adaptive immune response, infected BALB/c mice reproducibly recover from infection, consistent with prior studies on a related virus, mouse thymic virus (MTV). Herein we show that in contrast to published studies on MTV, MRV appears to robustly infect neonatal C57BL/6 (B6) mice causing severe depletion of thymocytes and peripheral T-cells. Moreover, B6 mice recovered from infection. We investigated the mechanism of thymocyte and T-cell loss, determining that the major thymocyte subsets were infected with MRV, however CD4+ and CD4+CD8− showed increased apoptosis during infection. We found that CD8+ T-cells populated MRV-infected thymi. These CD8+ T cells expressed markers of activation, had restricted T-cell receptor repertoire and accumulated intracellular effector proteins, consistent with a cytotoxic lymphocyte phenotype, and suggesting their involvement in viral clearance. Indeed, absence of CD8+ T-cells prevented recovery from MRV infection and led to lethality in infected animals whereas B-cell deficient mice showed CD4+ T-cell loss but recovered from infection without lethality. Thus these results demonstrate that CD8+ T-cells are required for protective immunity against a naturally occurring murine pathogen that infects the thymus, and establish a novel infection model for MRV in B6 mice, providing the foundation for detailed future studies on MRV with the availability of innumerable mutant mice on the B6 background.

Comparative Analysis of Roseoloviruses in Humans, Pigs, Mice, and Other Species

“…This appears to be a polyclonal and antigen restricted response [163]. Supporting an important role of CD8 + T cells in controlling MRV infection, CD8 knockout mice are unable to recover CD4 + T cell levels and have an 80% mortality after neonatal infection [163]. Of note, this demonstrates that CD4 + T cell depletion occurs independently of CD8 + T cells.…”

“…Transient necrosis of the lymph nodes and spleen also occur in MRV inoculated neonatal mice, which starts at day 7 and peaks at 14 dpi [161]. In these infected lymphoid organs, lymphocytes, epithelial reticular cells, macrophages, and thymic nurse cells contain viral particles and filamentous structures in both the nucleus and the cytoplasm [162,163]. By three weeks post-inoculation (wpi), the histology of the infected thymus becomes normal again [160], and the total number of cells in the mesenteric lymph node is recovered to the levels of normal mice [161].…”

“…By 6 wpi, the weight of the infected thymus is comparable to normal controls [150,160]. Interestingly, although both CD4 + and CD8 + cells get infected in the thymus and spleen, only the CD4 + CD8 + and CD4 + CD8 − lymphocytes are sensitive to apoptosis [162,163]. The loss of T lymphocytes apparently causes transient host immune suppression.…”

“…While MRV appears to have a significant effect on CD4 + T cells, CD8 + T cells are important for controlling MRV infection. After viral infection, there is an increase in activated/effector CD8 + T cells, as demonstrated by increased expression of activation markers CD44 and CD69, and effector molecules granzyme B and interferon gamma [163]. This appears to be a polyclonal and antigen restricted response [163].…”

“…After viral infection, there is an increase in activated/effector CD8 + T cells, as demonstrated by increased expression of activation markers CD44 and CD69, and effector molecules granzyme B and interferon gamma [163]. This appears to be a polyclonal and antigen restricted response [163]. Supporting an important role of CD8 + T cells in controlling MRV infection, CD8 knockout mice are unable to recover CD4 + T cell levels and have an 80% mortality after neonatal infection [163].…”