The clearance of apoptotic cells: implications for autoimmunity

Apoptosis has been clearly characterised by the ability to limit the activation of inflammatory responses through the disposal of the apoptotic cell by rapid uptake by phagocytes. The exposure of phosphatidylserine deriving from the loss of plasma lipid asymmetry is the early membrane signal which alerts the phagocyte about the imminent apoptotic death of the cell. Also modifications of membrane carbohydrate groups on apoptotic cells contribute to phagocyte recognition. Soluble proteins such as C1q, mannose-binding lectin, surfactant proteins A and D, C-reactive protein, C3bi, beta2-glycoprotein I and growth arrest specific gene-6 bind to apoptotic cells and act as "opsonins" thus favouring their clearance. A redundant and promiscuous system of receptors including integrins, scavenger receptors, CR3 and CR4, calreticulin, CD14 and Mer receptor ensures an efficient and rapid uptake of apoptotic cells. In animal models and in human pathology, single genetic defects of molecules involved in apoptotic cell clearance seem to be the main determinant in the development of autoimmunity. The uptake of apoptotic cells by phagocytes provides an immunomodulatory effect in that it triggers the release of anti-inflammatory cytokines, inhibits the production of inflammatory cytokines and leads to T cell tolerance. Impaired clearance of apoptotic cells or the presence of 'danger' signals may modify the balance between tolerance induction and activation of T cells leading to an effective autoimmune response.     

Immunoregulation of autoimmunity by natural killer T cells

Natural killer T (NKT) cells are a conserved subpopulation of lymphocytes that recognize glycolipid antigens in a CD1d context. Upon activation through their semi-invariant T cell receptor, these cells rapidly release large amounts of immunomodulating Th1 and Th2 cytokines. NKT cells have therefore been implicated in immune responses controlling various diseases, including infection, cancer, transplantation, and autoimmunity. Stimulation of the immunoregulatory capacity of NKT cells by the prototypical antigen -galactosylceramide results in amelioration of disease in several animal models. This review will focus on the current knowledge of human NKT cells and their role in autoimmune diseases. The features of these cells and their importance in regulation of autoimmunity suggest that NKT cell-based therapies might be an interesting approach for the treatment of autoimmune diseases.     

Fas ligand-dependent suppression of autoimmunity via recruitment and subsequent termination of activated T cells

Signals transmitted by binding of Fas ligand (FasL) to the Fas receptor (CD95/Apo-1) have pleiotropic effects on cellular function that present opportunities for therapeutic applications. For example, depending on the circumstances, overexpression of FasL can enhance, prevent, or reverse growth of spontaneous or transplantable tumors. Furthermore, local administration of FasL into a single paw in susceptible mice protects from or reduces the severity of collagen-induced arthritis (CIA) in all paws. Here, we define mechanisms that mediate systemic protection induced by locally delivered FasL. Protection is not solely dependent on local interactions between Fas and FasL, but rather requires induction of a paradoxical inflammatory response that not only destroys Fas-resistant tumors, but also recruits motile, activated, Fas-bearing T cells that are Fas sensitive. We demonstrate by following the antigen-specific recruitment and subsequent termination of transgenic T cells that activated T cells, including autoreactive cells responsible for CIA, are eliminated within this inflammatory environment through the overexpressed FasL. The nature of the inflammatory response, which depends on the Fas ligand being cell bound and not soluble, and the magnitude of FasL expression within the inflammatory milieu are essential for this effect, as arthritogenic inflammation alone resulting from CIA induction is insufficient to ameliorate the disease or eliminate antigen-specific T cells, even upon systemic delivery of soluble FasL. These data show that gene delivery of membrane-bound FasL can effectively recruit and eliminate autoreactive T cells.     

Tregs are regulated by cytokines: implications for autoimmunity

Several immune cell subsets contribute to the maintenance of peripheral tolerance by taking active participation in the networks that suppress autoreactive immune responses. There is ample evidence that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) can have an important role in suppressing the production of autoimmune responses in animal models and in humans. This review describes the influences that specific cytokines have on the differentiation, maintenance and survival of Tregs, and how these effects can ultimately directly influence both number and functional activity of these cells in autoimmune disease.     

Immunoregulatory T cells in autoimmunity

The aim of this work was to discuss the current knowledge concerning regulatory T cells in the pathogenesis of autoimmune diseases. CD4(+) T cells that constitutively express CD25 exhibit powerful suppressive properties. Such cells have been denominated regulatory T cells (T(R)). Alterations in T(R) cells are known to cause organ-specific autoimmune disease in animal models. These cells are anergic when stimulated via their TCR but proliferate when co-stimulated with IL-2. A particular characteristic is that CD4(+)CD25(+) T cells inhibit the proliferative responses of CD4(+)CD25(-) T cells by suppressing the capacity of the responders to transcribe IL-2. The survival and/or expansion of this regulatory subset in the periphery appears to need the availability of IL-2, the components of the IL-2R, as well as cell surface costimulatory molecules. Cytokine participation has been shown in many of the in vivo models of autoimmunity where regulatory cells participate, providing evidence in favour of a role for IL-10, transforming growth factor-beta and IL-4. The behavior and possible participation of regulatory T cells in human disease is still a poorly explored topic but their pathogenic role is warranted.     

Human regulatory T cells and autoimmunity

CD4+CD25+ regulatory T cells (Treg) appear to be critical in regulating immune responses to self-antigens. Treg deficiency is associated with several human autoimmune diseases. Although substantial progress has been made in the study of murine and human Treg, their fundamental mechanism of action remains unknown. In this review, we discuss the phenotype of human natural Treg, their functional mechanism, and their role in autoimmune disease.     

Natural regulatory T cells in autoimmunity

The suppressive/immunomodulatory function of CD4(+)CD25(+)FOXP3(+) regulatory T (Treg) cells is crucial for the maintenance of immune homeostasis, which helps to prevent autoimmunity and reduce the inflammation induced by pathogens and environmental insults. This review summarizes the current knowledge on the types and mechanisms of action of Treg cells and their role in the immune tolerance to self-antigens, with a particular focus on naturally occurring Treg cells.     

gamma delta T cells in autoimmunity

Conclusions  γδ T cells likely play a critical role in the host defenses, and recent evidence has indicated they are important in regulation of the immune response after pathogen challenge. Data are also accumulating that they play a part in autoimmunity and immune regulation. Evidence indicates that γδ T cells mediate these effects through cytokine production, via direct effects on cells of the adaptive immune response, or through interactions with innate immune components or barriers. Nevertheless, the biological function of γδ T cells in immune responses, especially in autoimmunity, largely remains unresolved. Further studies are needed to gain more knowledge about the immunobiology of these cells, asking why precisely they bear an activated phenotype in vivo, how their cytokine production is regulated, and how they interact with other cells of the innate and adaptive immune responses.     

Self-antigen presentation by dendritic cells and lymphoid stroma and its implications for autoimmunity

The induction and maintenance of T cell tolerance is essential to prevent autoimmunity. A combination of central and peripheral mechanisms acts to control autoreactive T cells. In secondary lymphoid organs, dendritic cells (DCs) presenting self-antigen were thought to play a major role in the induction of peripheral T cell tolerance. Multiple recent studies have demonstrated that DCs are not absolutely essential to induce and maintain tolerance. Furthermore, it has also been recently shown that non-hematopoietic stromal cells expressing peripheral tissue-restricted antigens can induce T cell tolerance, independently of DCs. Together these studies imply that peripheral tolerance is more complex than previously thought and a consequence of the tolerogenic functions of the hematopoietic and non-hematopoietic compartments within secondary lymphoid organs.     

The leptin connection: regulatory T cells and autoimmunity

Leptin is a cytokine-like hormone with proinflammatory properties linked to autoimmune diseases. In this issue of Immunity, De Rosa et al. (2007) elucidate an important new role for leptin in the anergy and hyporesponsiveness of regulatory T cells.     

Idiotype usage by polyclonally activated B cells in experimental autoimmunity and infection

Both in animal models and in human systemic lupus erythematosus (SLE) the occurrence of nephritogenic autoantibodies bearing dominant idiotypes has been described. In this study we investigate the relation between the induction pathway of polyclonal B cell activation and the production and glomerular deposition of nephritogenic antibodies with shared dominant idiotype(s). Polyclonal B cell activation was induced in several experimental models characterized by glomerular immune deposit formation. We monitored the occurrence of dominant idiotypes among immunoglobulins deposited in the glomeruli. In addition, we studied the species specificity of the dominant idiotypes, by monitoring their presence in kidney sections of patients with an immunologically mediated kidney disease. Anti-idiotype antisera against two monoclonal anti-DNA autoantibodies were used, derived from MRL-lpr/lpr mice, i.e. clone H241 and clone H130. Autoantibodies with the H241 idiotype were present in immune complex depositions in all experimental models but not in humans. We therefore conclude that the presence of this dominant idiotype is independent of the induction pathway of polyclonal B cell activation. However, autoantibodies bearing the H130 idiotype were only detected in kidney sections of mice with spontaneous lupus.     

CD8+ T cells in autoimmunity

Mounting evidence shows that CD8(+) T cells contribute to the initiation, progression and regulation of several pathogenic autoimmune responses in which these cells were not previously thought to play a major role. CD8(+) T cells can kill target cells directly, by recognizing peptide-MHC complexes on target cells, or indirectly, by secreting cytokines capable of signaling through death receptors expressed on the target cell surface. Autoreactive CD8(+) T cells can also contribute to autoimmunity by releasing cytokines capable of increasing the susceptibility of target cells to cytotoxicity, or by secreting chemokines that attract other immune cells to the site of autoimmunity. Autoreactive CD8(+) T cells can also downregulate autoimmune responses. Recent important advances include a mechanistic understanding of events leading to the activation and recruitment of autoreactive CD8(+) T cells in certain autoimmune responses and a greater appreciation of the diverse roles that these T cells play in autoimmunity.     

T cell immunity in hepatitis B and hepatitis C virus infection: implications for autoimmunity

T cells are involved in the pathogenesis of important liver diseases including both autoimmune liver diseases and viral hepatitis. In addition to playing a crucial role in the control of hepatitis viruses, T cell responses are also responsible for the liver injury during acute and chronic phases of viral hepatitis. In this article, we reviewed current literature on T cell immunity to hepatitis B and C viruses. In addition, antigen presenting cells that are critical for T cell immunity against these viruses are also discussed. This will provide insights to the understanding of T cell immunity in autoimmune liver diseases due to the similar role of T cells in autoimmune liver diseases and viral hepatitis.     

Committed to memory: lineage choices for activated T cells

The mechanisms for the generation of memory T cells and their delineation into heterogeneous subsets remain unknown. The linear model for memory T-cell generation from differentiated effector cells has been favored, although there is evidence that memory T cells can emerge directly from naive T cells undergoing homeostatic expansion and from activated T cells lacking effector functions. Here, we discuss the evidence from diverse studies of memory generation that support a new 'intersecting pathway' model for memory T-cell generation in which antigen-driven effector differentiation and homeostasis-driven memory differentiation follow distinct but analogous pathways. Antigen withdrawal during effector differentiation enables intersection with the memory pathway through a pre-memory intermediate, and memory heterogeneity is influenced by homeostasis, migration and persistence in vivo.     

Why aging T cells fail: implications for vaccination

The decline in CD4+ T cell function with aging contributes to reduced vaccine efficacy. In this commentary, we discuss the factors leading to age-related changes in T cell function and propose how they may be overcome to enhance vaccine efficacy for the elderly.