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

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

Giant cell arteritis: immune and vascular aging as disease risk factors

Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche

Activation of Arterial Wall Dendritic Cells and Breakdown of Self-tolerance in Giant Cell Arteritis

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4+ T cells are selectively activated in the adventitia of affected arteries. In human GCA artery–severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83+ dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia–media border. Adoptive T cell transfer into temporal artery–SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II–matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space