[Show abstract][Hide abstract] ABSTRACT: Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
Journal of Experimental Medicine 03/2011; 208(4):775-85. DOI:10.1084/jem.20100031 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD85j (ILT2/LILRB1/LIR-1) is an inhibitory receptor that recognizes major histocompatibility complex (MHC) class Ia and Ib alleles that are widely expressed on all cell types. On ligand recognition, CD85j diminishes kinase activity by recruiting phosphatases to motifs within its cytoplasmic domain. Within the hematopoietic system, CD85j is expressed with cell-specific patterns and cell surface densities that reflect the different roles of cell contact-mediated inhibition in these lineages. While monocytes ubiquitously have high cell surface expression, B lymphocytes start to express CD85j at intermediate levels during early B-cell maturation and natural killer (NK) cells and T cells exhibit a low level of expression on only a subset of cells. The cell-specific expression pattern is accomplished by 2 complementing but not independent mechanisms. Lymphocytes and monocytes use distinct promoters to drive CD85j expression. The lymphocyte promoter maps 13 kilobases (kb) upstream of the monocyte promoter; its use results in the inclusion of a distant exon into the 5'-untranslated region. A short sequence stretch within this exon has the unique function of repressing CD85j protein translation and is responsible for the subdued expression in lymphocytes. These cell-specific mechanisms allow tailoring of CD85j levels to the distinct roles it plays in different hematopoietic lineages.
[Show abstract][Hide abstract] ABSTRACT: Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because 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 preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, 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 crosstalk pathways may provide pharmacological targets for bone anabolism.
[Show abstract][Hide abstract] ABSTRACT: A fundamental feature of mammalian adaptive immunity is the highly diverse pool of antigen receptors found on lymphocytes.
The T-cell receptor and the surface immunoglobulin on B cells facilitate the recognition of foreign structures found on tumors
and pathogens that have overwhelmed the defenses of the innate immune system. Because pathogen encounters and neoplasic transformations
are inherently unpredictable, an immense lymphocyte receptor repertoire is required to meet all of the possible challenges
an organism will face. In young humans, the daily production of naïve B cells from the bone marrow and T cells from the thymus
steadily injects the lymphocyte pool with new antigen receptors. Unfortunately, as humans age functional thymic tissue gradually
involutes and is replaced by fat. In parallel, the daily production of new naïve T cells declines such that no meaningful
thymic T-cell production occurs after the age of fifty. Thus, the T-cell repertoire of an adult human must be maintained for
decades in the absence of a replenishing source. Although homeostatic mechanisms are remarkably successful at maintaining
the T-cell repertoire for many years, obvious changes begin to emerge with advanced age. Most strikingly, the naïve CD4 T
cells that remain after the age of 65 undergo a sudden and dramatic collapse of T-cell receptor diversity. Naïve CD8 T cells
may experience an earlier and more gradual diversity loss, although direct evidence for this is not yet available. A steadily
expanding memory population maintains total T-cell numbers despite the decline in naïve T cells. Among these memory cells,
an increasing percentage acquires a terminally differentiated phenotype characterized by abnormal expression of regulatory
receptors and resistance to apoptosis. Oligoclonal populations accumulate after a lifetime of repeated challenges such as
chronic infections, leading to a contracted memory repertoire. Although the consequences of repertoire contraction are not
yet known, this phenomenon may have important implications for the health of the ever growing elderly population.
[Show abstract][Hide abstract] ABSTRACT: 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 cross-sectional 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.