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CD8+ T Cells Prevent Lethality from Neonatal Murine Roseolovirus Infection
Swapneel J Patel1, Wayne M Yokoyama2,3
1Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
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. In this article, we show that, in contrast to published studies on mouse thymic virus, 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- T cells 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 TCR 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.
Insights
Murine roseolovirus (MRV) infects neonatal mice, causing T cell loss. CD8+ T cells are crucial for clearing the infection and enabling recovery, highlighting their role in protective immunity against this thymus-infecting pathogen.
Area of Science:
- Immunology
- Virology
- Mouse Models
Background:
- Murine roseolovirus (MRV), a mouse homolog of human roseoloviruses, causes CD4+ T cell depletion in neonatal BALB/c mice.
- While BALB/c mice recover from MRV infection, the virus's impact on C57BL/6 (B6) mice and the underlying mechanisms of T cell loss were unclear.
Purpose of the Study:
- To investigate MRV infection in neonatal C57BL/6 (B6) mice.
- To elucidate the mechanisms of thymocyte and T cell depletion during MRV infection.
- To determine the role of CD8+ T cells in recovery from MRV infection.
Main Methods:
- Neonatal C57BL/6 (B6) mice were infected with MRV.
- Flow cytometry and intracellular protein staining were used to analyze thymocyte and peripheral T cell populations.
- Apoptosis assays were performed to assess T cell death.
- Experiments using CD8+ T cell-deficient and B cell-deficient mice were conducted.
Main Results:
- MRV robustly infected neonatal B6 mice, causing severe depletion of thymocytes and peripheral T cells, including CD4+ and CD4+CD8- T cells, which showed increased apoptosis.
- MRV-infected thymi were populated by activated CD8+ T cells with a restricted TCR repertoire and effector functions, suggesting a cytotoxic role.
- Absence of CD8+ T cells prevented MRV recovery and led to lethality.
- B cell-deficient mice experienced CD4+ T cell loss but recovered without lethality.
Conclusions:
- CD8+ T cells are essential for protective immunity and recovery from MRV infection in B6 mice.
- MRV infection in B6 mice establishes a new model for studying roseolovirus pathogenesis and host immune responses.
- This study highlights the critical role of CD8+ cytotoxic lymphocytes in controlling naturally occurring viral infections affecting the thymus.
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