IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection.

IL-27 exerts pleiotropic suppressive effects on naive and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4+ T cell chemotactic responses, as a mechanism to reduce T cell–dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, proinflammatory infection, we demonstrate that IL-27R signaling represses chemotaxis of infection-derived splenic CD4+ T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4+ T cells from malaria-infected, IL-27R–deficient (WSX-1−/−) mice than from infected wild-type mice. We find that IL-27 signaling suppresses splenic CD4+ T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4+ T cell subtypes, including Th1 cells, and also by controlling the overall composition of the CD4+ T cell compartment. Diminution of the Th1 response in infected WSX-1−/− mice in vivo by neutralization of IL-12p40 attenuated CCR5 expression by infection-derived CD4+ T cells and also reduced splenic CD4+ T cell chemotaxis toward CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4+ T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings

Infection-induced resistance to experimental cerebral malaria is dependent upon secreted antibody-mediated inhibition of pathogenic CD8(+) T cell responses

Cerebral malaria (CM) is one of the most severe complications of Plasmodium falciparum infection. There is evidence that repeated parasite exposure promotes resistance against CM. However, the immunological basis of this infection-induced resistance remains poorly understood. Here, utilizing the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (ECM), we show that three rounds of infection and drug-cure protects against the development of ECM during a subsequent fourth (4X) infection. Exposure-induced resistance was associated with specific suppression of CD8+ T cell activation and CTL-related pathways, which corresponded with the development of heterogeneous atypical B cell populations as well as the gradual infection-induced generation and maintenance of high levels of anti-parasite IgG. Mechanistically, transfer of high-titer anti-parasite IgG did not protect 1X infected mice against ECM and depletion of atypical and regulatory B cells during 4X infection failed to abrogate infection-induced resistance to ECM. However, IgMi mice that were unable to produce secreted antibody, or undergo class switching, during the repeated rounds of infection failed to develop resistance against ECM. The failure of infection-induced protection in IgMi mice was associated with impaired development of atypical B cell populations and the inability to suppress pathogenic CD8+ T cell responses. Our results, therefore, suggest the importance of anti-parasite antibody responses, gradually acquired, and maintained through repeated Plasmodium infections, for modulating the B cell compartment and eventually suppressing memory CD8+ T cell reactivation to establish infection-induced resistance to ECM

WISP-1 drives bone formation at the expense of fat formation in human perivascular stem cells

Abstract The vascular wall within adipose tissue is a source of mesenchymal progenitors, referred to as perivascular stem/stromal cells (PSC). PSC are isolated via fluorescence activated cell sorting (FACS), and defined as a bipartite population of pericytes and adventitial progenitor cells (APCs). Those factors that promote the differentiation of PSC into bone or fat cell types are not well understood. Here, we observed high expression of WISP-1 among human PSC in vivo, after purification, and upon transplantation in a bone defect. Next, modulation of WISP-1 expression was performed, using WISP-1 overexpression, WISP-1 protein, or WISP-1 siRNA. Results demonstrated that WISP-1 is expressed in the perivascular niche, and high expression is maintained after purification of PSC, and upon transplantation in a bone microenvironment. In vitro studies demonstrate that WISP-1 has pro-osteogenic/anti-adipocytic effects in human PSC, and that regulation of BMP signaling activity may underlie these effects. In summary, our results demonstrate the importance of the matricellular protein WISP-1 in regulation of the differentiation of human stem cell types within the perivascular niche. WISP-1 signaling upregulation may be of future benefit in cell therapy mediated bone tissue engineering, for the healing of bone defects or other orthopaedic applications

Career Development and Aging

Career development and aging represents a topic of growing importance for individuals as well as organizations. As society and the workforce is aging, late career employees embody a steadily growing proportion of the working population (Van der Heijden, Schalk, & Van Veldhoven, 2008). In order to create and maintain a successful and satisfying late career, this population has to successfully deal with today’s changing work environment and its demands. In this chapter, first a review traditional stage-based models of late career development is given. Then an overview of how the current work environment increasingly necessitates a protean career orientation and career adaptability among older workers is provided. The chapter concludes with implications for career counseling and HR practices regarding older workers