gms | German Medical Science

Objectives: Polymicrobial sepsis, a systemic bacterial infection, induces a state of immunosuppression. This enhances the susceptibility to secondary infections, but has been described as less severe in TLR2 knockout (ko) mice. Immunosuppression is associated with reprogramming of myeloid cells which differentiate in the bone marrow depending on the cytokine microenvironment. We postulate that changes in the bone marrow are responsible for the development of post-septic immunosuppression. Previous work has shown the accumulation of activated T cells in the bone marrow within 24 hours after the onset of sepsis which contrasts sepsis-induced T cell apoptosis in the spleen. T cells, especially CD8+ virtual memory T cells, are activated independent of their cognate antigen by exposure to innate cytokines (termed „bystander“ activation). In this study, CD8+ T cells in the bone marrow and a possible role of bystander activation during sepsis was examined.

Methods: Polymicrobial sepsis was induced by cecal ligation and puncture in wildtype BALB/c mice and TLR2 ko mice. Twenty-four hours after sepsis induction, bone marrow cells were isolated and analyzed regarding composition of different T cell subsets as well as the activation level and functionality of these cells. Conditioned media from bone marrow cultures were prepared 12 hours after surgery and were subjected to a protein array.

Results and conclusion: The number of naÏve, central memory, and virtual memory CD8+ T cells but not of effector/effector memory CD8+ T cells significantly increased in the bone marrow. Additionally, the number of CD69 expressing central memory and virtual memory CD8+ T cells increased indicating activation of these cells. No difference in T cell accumulation and activation could be identified between wildtype and TLR2 ko mice. However, effector/effector memory CD8+ T cells showed an impaired ability to produce Interferon gamma (IFN-g) in wildtype but not in TLR2 ko mice and instead produced Interleukin 10. When adoptively transferred into wildtype mice, CD8+ T cells from TLR2 ko mice maintained their superior capacity for IFN-g production. Various proteins that are known to attract and modulate T cells were secreted by bone marrow cells during sepsis (12 hours after surgery).

Polymicrobial sepsis induces an accumulation of antigen-independently activated CD8+ T cells in the bone marrow. Thereby, so far unknown TLR2 ligands modulate the cytokine secretion pattern of the CD8+ T cells. Since the cytokine environment plays a crucial role in the differentiation process in the bone marrow, the alteration of CD8+ T cells might contribute to the reprogramming of myeloid cells during sepsis.