T-cell co-stimulatory pathways in autoimmunity

T-cell activation and differentiation depend on the signal strength received by the T-cell receptor and on signals provided by co-stimulatory molecules. The most prominent co-stimulatory molecule is CD28, which controls the activation of naïve and memory T cells by antigen presented on professional antigen-presenting cells. Blocking of the CD28-CD80/86 pathway has been an appealing strategy for inducing tolerance in autoimmune diseases where the disease-inducing autoantigens are not known. Although CD28 has maintained its unique position, the past decade has witnessed the recognition that a large number of regulatory molecules on T cells must be stimulated to generate a fully protective immune response. These regulatory receptors differ in their preferential expression on T-cell subsets, in the ligands that they recognize, and in the signaling pathways that they trigger. They have in common the fact that they provide information on the cellular environment in which the T-cell response occurs. By intercepting these signals, we may be able to influence disease-relevant T-cell responses in autoimmune diseases while potentially minimizing broad immunosuppression

Developments in the scientific understanding of rheumatoid arthritis

Rheumatoid arthritis (RA) is recognized to be an autoimmune disease that causes preclinical systemic abnormalities and eventually leads to synovial inflammation and destruction of the joint architecture. Recently identified genetic risk factors and novel insights from animal models of spontaneous arthritis have lent support to the concept that thymic selection of an autoreactive T-cell repertoire is an important risk factor for this disease. With advancing age, defects in the homeostatic control of the T-cell pool and in the setting of signaling thresholds lead to the accumulation of pro-inflammatory T-effector cell populations and loss of tolerance to neo-antigens, such as citrullinated peptides. As the breakdown of tolerance to modified self-antigens can precede synovitis by decades, repair of homeostatic defects may open a unique window of opportunity for preventive interventions in RA. The end result of RA, destruction of cartilage and bone, appears to be driven by cytokine- and cell contact-induced activation of synoviocytes and monocytic cells, some of which differentiate into tissue-destructive osteoclasts. Targeting mediators involved in this process has greatly improved the management of this chronic inflammatory syndrome

Light interception, gas exchange and carbon balance of different canopy zones of minimally and cane-pruned field-grown Riesling grapevines

Leaf area development, pre-dawn leaf water potential, spatial and temporal patterns of light interception and photosynthesis (A) of minimal pruned (MP) and cane-pruned vertical shoot positioned (VSP) fieldgrown Riesling grapevines were monitored in 2002 and 2003. In order to quantify the contribution of different canopy segments to whole vine carbon gain, diurnal single leaf gas exchange measurements were conducted several times during the season in 8 different canopy segments keeping leaves in their natural position. Carbon losses due to nocturnal respiration (DR) were estimated with a model describing the dependence of DR on temperature. MP vines had about 17 times more but less vigorous shoots with smaller leaves. Leaf area (LA) development was faster for MP than for VSP vines and LA was 2.5-3-fold higher for most of the season. Spatial and temporal patterns of average daily light interception were related to LA development and canopy dimensions for both MP and VSP vines during the first part of the season, but increased independent of LA until mid-October and more so for VSP than MP. Diurnal gas exchange measurements showed differences between canopy segments, measuring dates and systems. Differences between segments were related to light interception in the absence of water deficit, high leaf temperature and vapour pressure deficit. The higher light interception of MP vines caused pre-dawn water potential to decrease faster and to remain at lower levels during most of the season. This limited A more severely for leaves of MP vines in canopy segments which were well exposed to light. The estimated seasonal carbon gain per canopy segment was highest in the apical canopy zones for both canopy systems but carbon assimilation was higher for MP than for VSP vines in all segments with the exception of the interior canopy. Respiratory losses by leaves depended on night temperature and time during the season but generally varied between 3 and 7 % of the amount of carbon gained during the day. MP vines had slightly higher relative respiration losses than VSP vines. On a whole-plant basis, carbon gain of MP vines was between 5.7 (beginning of the season) and 2.2 times (end of season) higher than for VSP vines.

B cells in rheumatoid synovitis

In rheumatoid arthritis, T cells, B cells, macrophages, and dendritic cells invade the synovial membranes, establishing complex microstructures that promote inflammatory/tissue destructive lesions. B cell involvement has been considered to be limited to autoantibody production. However, recent studies suggest that B cells support rheumatoid disease through other mechanisms. A critical element of rheumatoid synovitis is the process of ectopic lymphoid neogenesis, with highly efficient lymphoid architectures established in a nonlymphoid tissue site. Rheumatoid synovitis recapitulates the pathways of lymph node formation, and B cells play a key role in this process. Furthermore, studies of rheumatoid lesions implanted in immunodeficient mice suggest that T cell activation in synovitis is B cell dependent, indicating the role played by B cells in presenting antigens and providing survival signals

Heterogeneity of Memory T Cells in Aging

Immune memory is a requisite and remarkable property of the immune system and is the biological foundation of the success of vaccinations in reducing morbidity from infectious diseases. Some vaccines and infections induce long-lasting protection, but immunity to other vaccines and particularly in older adults rarely persists over long time periods. Failed induction of an immune response and accelerated waning of immune memory both contribute to the immuno-compromised state of the older population. Here we review how T cell memory is influenced by age. T cell memory is maintained by a dynamic population of T cells that are heterogeneous in their kinetic parameters under homeostatic condition and their function. Durability of T cell memory can be influenced not only by the loss of a clonal progeny, but also by broader changes in the composition of functional states and transition of T cells to a dysfunctional state. Genome-wide single cell studies on total T cells have started to provide insights on the influence of age on cell heterogeneity over time. The most striking findings were a trend to progressive effector differentiation and the activation of pro-inflammatory pathways, including the emergence of CD4+ and CD8+ cytotoxic subsets. Genome-wide data on antigen-specific memory T cells are currently limited but can be expected to provide insights on how changes in T cell subset heterogeneity and transcriptome relate to durability of immune protection