engleski

NKG2D PROMOTES B1A CELL DEVELOPMENT AND ENHANCES PROTECTION AGAINST BACTERIAL INFECTION

NKG2D-deficiency affects both development and function of NK cells in mice. Previously, we have shown that also the B cell compartment of NKG2D-deficient mice is affected but the mechanism remained unknown. This prompted us to study the role of NKG2D on B cell development and function. Histological sections of spleen and lymph node tissue showed no clear difference in structures of B cell follicles between WT and NKG2D-deficient mice. However, FACS analysis revealed that both frequency and absolute number of splenic B cells were reduced. Strikingly, in the peritoneal cavity of NKG2D-deficient animals, we observed that the number of B1a cells was significantly reduced. Homeostatic proliferation and survival properties of NKG2D-deficient B cells from peritoneum were not changed. Moreover, B1a cells from NKG2D-/- mice were not functionally impaired. However, mixed bone marrow and fetal liver chimeras showed that NKG2D-deficient bone marrow precursor cells have a reduced capacity to generate B1a cells. Since we did not observe NKG2D expression on any mature or precursor B cell population, we hypothesized that NKG2D affects early hematopoietic development. Indeed, full NKG2D knock-out mice, but not animals lacking NKG2D only in the CD19-expressing cell lineage showed a reduction of B1a cells in their peritoneal cavity. This indicates a role for NKG2D during the earliest stages of B cell development. Finally, we tested the clinical relevance of the reduced number of peritoneal B1a cells in NKG2D-deficient mice. We found that NKG2D-/- mice are less capable of clearing the highly pathogenic bacterium, Francisella novicida upon intraperitoneal infection. We also found that upon induction of sepsis with the cecal ligation and puncture model, NKG2D-deficient mice were much more susceptible to peritonitis and had a higher mortality rate. The observed effects were B cell dependent, since genetic deletion of these cells in NKG2D-deficient animals did not further increase their sensitivity to bacterial infection. In summary, we here report that NKG2D deficiency results in impaired B cell development which leads to lower number of B1a cells in peritoneal cavity. Ultimately, this results in a reduced ability of the B cell compartment to fight bacterial infections.

NKG2D; B1; B cell development

nije evidentirano