The extensive somatic diversification of immune receptors is a hallmark of higher vertebrates. However, whether molecular diversity contributes to immune protection in invertebrates is unknown. We present evidence that Drosophila immune-competent cells have the potential to express more than 18,000 isoforms of the immunoglobulin (Ig)-superfamily receptor Down syndrome cell adhesion molecule (Dscam). Secreted protein isoforms of Dscam were detected in the hemolymph, and hemocyte-specific loss of Dscam impaired the efficiency of phagocytic uptake of bacteria, possibly due to reduced bacterial binding. Importantly, the molecular diversity of Dscam transcripts generated through a mechanism of alternative splicing is highly conserved across major insect orders, suggesting an unsuspected molecular complexity of the innate immune system of insects.

With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In crosssectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.

Summary Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis as it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells, and induces these lymphocytes to activate canonical Wnt-signaling in pre-osteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in pre-osteoblasts and blunted osteoblastic commitment, proliferation, differentiation and lifespan which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T cell produced Wnt10b. Therefore, T cell mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast cross-talk pathways may provide pharmacological targets for bone anabolism.

Zinc enhances TCR signaling in part by inhibiting Shp-1 recruitment to the TCR synapse.