The bone marrow (BM) plays a key role in the long‐term maintenance of immunological memory. However, the impact of aging on the production of survival factors for effector/memory T cells and plasma cells in the human BM has not been studied. We now show that the expression of molecules involved in the maintenance of immunological memory in the human BM changes with age. While IL‐15, which protects potentially harmful CD8⁺CD28⁻ senescent T cells, increases, IL‐7 decreases. IL‐6, which may synergize with IL‐15, is also overexpressed. In contrast, a proliferation‐inducing ligand, a plasma cell survival factor, is reduced. IFN‐y, TNF, and ROS accumulate in the BM in old age. IL‐15 and IL‐6 expression are stimulated by IFN‐y and correlate with ROS levels in BM mononuclear cells. Both cytokines are reduced by incubation with the ROS scavengers N‐acetylcysteine and vitamin C. IL‐15 and IL‐6 are also overexpressed in the BM of superoxide dismutase 1 knockout mice compared to their WT counterparts. In summary, our results demonstrate the role of inflammation and oxidative stress in age‐related changes of immune cell survival factors in the BM, suggesting that antioxidants may be beneficial in counteracting immunosenescence by improving immunological memory in old age.

The bone marrow (BM) is a major reservoir of resting memory T cells and long-lived plasma cells, capable of providing protection against recurrent infections. Whether the age-related accumulation of adipose tissue in the BM affects the functionality and maintenance of memory cells is not well understood. For the first time, we compare human femur marrow adipose tissue (fMAT) and subcutaneous white adipose tissue of the thigh (tsWAT) obtained from the same donors. Therefore, we used microarrays for comparative global gene expression analysis, and employed assays to analyse parameters of adipocyte biology, inflammation and oxidative stress. We show that fMAT adipocytes differ significantly from tsWAT adipocytes regarding specific gene expression profiles including inflammatory responses and adipogenesis/adipocyte phenotype. Concomitant with considerably lower levels of CD36, a membrane-associated protein important for long-chain fatty acid uptake that is used as maturation marker, fMAT adipocytes are smaller and contain less triglycerides. fMAT adipocytes secrete similar levels of adiponectin and leptin as tsWAT adipocytes, and express increased levels of pro-inflammatory molecules concomitant with an elevated generation of reactive oxygen species (ROS) and impaired function of plasma cells in the BM. Our findings suggest that fMAT is a unique type of adipose tissue containing small adipocytes with lower CD36 protein and triglyceride levels than tsWAT but high adipokine secretion. Moreover, fMAT adipocytes secrete high levels of pro-inflammatory cytokines, contributing to inflammation and impairment of plasma cell function in the BM, suggesting that fMAT has more immune regulatory functions than tsWAT.

Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso-deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso(-/-) mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso(-/-) mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso(-/-) mice succumbed to infections of L. monocytogenes, whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock.

Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8+ T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8+ T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8+ T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8+ T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8+ TEMRA cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Rα in CD8+ TEMRAbright cells. Increased IL-15 mRNA levels were observed in the BM of CMV+ compared to CMV- persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8+ T cells generated after CMV infection.

The innate immune response mediated by cells such as natural killer (NK) cells is critical for the rapid containment of virus replication and spread during acute infection. Here, we show that subtype 11 of the type I interferon (IFN) family greatly potentiates the antiviral activity of NK cells during retroviral infection. Treatment of mice with IFN-α11 during Friend retrovirus infection (FV) significantly reduced viral loads and resulted in long-term protection from virus-induced leukemia. The effect of IFN-α11 on NK cells was direct and signaled through the type I IFN receptor. Furthermore, IFN-α11-mediated activation of NK cells enabled cytolytic killing of FV-infected target cells via the exocytosis pathway. Depletion and adoptive transfer experiments illustrated that NK cells played a major role in successful IFN-α11 therapy. Additional experiments with Mouse Cytomegalovirus infections demonstrated that the therapeutic effect of IFN-α11 is not restricted to retroviruses. The type I IFN subtypes 2 and 5, which bind the same receptor as IFN-α11, did not elicit similar antiviral effects. These results demonstrate a unique and subtype-specific activation of NK cells by IFN-α11. The innate immune response mediated by cells such as natural killer (NK) cells can contribute to immunity against viral infections. NK cells can kill virus-infected cells and thus inhibit virus replication and spread during acute infection. However, in infections with retroviruses, like HIV, these cells are not sufficient to prevent pathology. Here, we describe a new strategy to augment natural killer cell responses during virus infections by using a subtype of the type I interferon family as antiviral drug. This therapy strongly activated NK cells and enabled them to control retrovirus as well as herpes virus infections in mice. The new approach might have great potential for the treatment of many infectious and tumor diseases in which natural killer cells play a significant role in immunity.

Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα–deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα–deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.