Presentation of neuroendocrine self in the thymus: toward a novel type of vaccine/immunotherapy

Slightly after the emergence some 400 millions years ago of the first signs of adaptive immune response, tolerogenic pathways developed in order to preserve the integrity of self from potential autoimmune toxicity. Amongst those tolerogenic pathways, the thymus occupies a central place both by deleting self-reactive T cells that are produced in the thymus during random recombination of gene segments encoding the variable parts of the T-cell receptor for antigen (TCR) (negative selection), and by generating self-antigen specific regulatory T cells (Tr). A repertoire of neuroendocrine-related genes are transcribed by thymic stromal cells — epithelial and ‘nurse’ cells (TEC/TNC), dendritic cells (DC) and macrophages (MF) — in such a way that a dominant protein precursor is expressed in the thymus environment. Oxytocin (OT) and neurokinin A (NKA) are the dominant thymic precursors for the neurohypophysial hormone and tachykinin families, respectively. With regard to the insulin gene family, all members are transcribed following a precise cell topography and hierarchy in the profile of gene expression: IGF2 (TEC/TNC) > IGF1 (MF) >> INS (medullary TEC and/or DC). This hierarchy implies that IGF-2 is more tolerated than IGF-1, and much more than Insulin (Ins). The low level of INS transcription in the thymus also explains why Ins displays immunogenic properties, as well as the significant prevalence (±40%) of anti-Ins autoantibodies in the general population. Ins administration failed in providing tolerance or protection toward islet ß cells in type 1 diabetes (T1D). In contrast, the presentation of IGF-2 B11-25, the homologous sequence of Ins B9-23, to peripheral blood mononuclear cells (PBMC) isolated from DQ8+ T1D adolescents significantly increases IL-10 secretion and IL10 expression. Given the potent regulatory/suppressive properties of IL-10 on the autoimmune response toward islet ß cells, these data support that IGF-2 derived sequences constitute a strong basis for the development of an antigen-specific driven tolerogenic approach for T1D prevention and/or cure.Peer reviewe

Importance of a Thymus Dysfunction in the Pathophysiology of Type 1 Diabetes

peer reviewedThe autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related autoantigens (insulin, GAD65 and phosphatase IA-2), the origin of this immune dysregulation still remains unknown. More and more evidence supports a thymic dysfunction in the establishment of central self-tolerance to the insulin family as a crucial factor in the development of the autoimmune response selective of pancreatic insulin-secreting islet beta cells. All the genes of the insulin family (INS, IGF1 and IGF2) are expressed in the thymus network. However, IGF-2 is the dominant member of this family first encountered by T cells in the thymus, and only IGFs control early T-cell differentiation. IGF2 transcription is defective in the thymus in one animal model of type 1 diabetes, the Bio-Breeding (BB) rat. The sequence B9-23, one dominant autoantigen of insulin, and the homologous sequence B11-25 derived from IGF-2 exibit the same affinity and fully compete for binding to DQ8, one class-II major histocompatibility complex (MHC-II) conferring major genetic susceptibility to type 1 diabetes. Compared to insulin B9-23, the presentation of IGF-2 B11-25 to peripheral mononuclear cells (PBMCs) isolated from type 1 diabetic DQ8+ adolescents elicits a regulatory/tolerogenic cytokine profile (*IL-10, *IL-10/IFN-g, *IL-4). Thus, administration of IGF-2 derived self-antigen(s) might constitute a novel form of vaccine/immunotherapy combining both an antagonism for the site of presentation of a susceptible MHC allele, as well as a downstream tolerogenic/regulatory immune response

Aire and Foxp3 expression in a particular microenvironment for T-cell differentiation

peer reviewe

Central self-tolerance by thymic presentation of self-antigens and autoimmunity

Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves inactivating mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T cells. During ontogeny, T cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes at the molecular level the dual role of the thymus in T cell negative and positive selection. Thymic precursors not only constitute a source of growth peptides for cryptocrine signaling between thymic stromal cells and pre-T cells, but are also processed in a way that leads to the presentation of self-antigens by thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases

Dendritic cell differentiation and immune tolerance to insulin-related peptides in Igf2-deficient mice

There is some evidence that insulin-like growth factor 2 (IGF-2) may intervene in the control of T cell differentiation. To further study the immunoregulatory function of this growth factor, we analyzed the immune system of Igf2(-/-) mice. Phenotypically, some immunological parameters such as lymphoid organ morphology and cellularity were unaltered in Igf2(-/-) mice, but an increase of CD8(+) cells and a decrease of B220(+) cells were observed in spleen. In vitro, the development of bone marrow-derived dendritic cells was affected by the absence of Igf2 expression. After maturation, a higher percentage of immature dendritic cells was observed in Igf2(-/-) population, together with a secondary decrease in allogenic T cell proliferation. Activation of T cells was also affected by the lack of expression of this growth factor. The profile of B cell response in mutant mice immunized with IGF-2 evidenced a T-dependent profile of anti-IGF-2 Abs that was absent in Igf2(+/+) mice. The influence of IGF-2 upon tolerance to insulin was also assessed in this model, and this showed that IGF-2 also intervenes in tolerance to insulin. The presence of a T-dependent response in Igf2-deficient mice should allow cloning of specific "forbidden" T CD4(+) lymphocytes directed against IGF-2, as well as further investigation of their possible pathogenic properties against insulin family

Thymus and T cells

Evidence for intimate interconnections between the three major systems of cell communication, the nervous, endocrine and immune systems, has opened important novel research perspectives. Neuroimmune-endocrine interactions are now established as crucial factors for the control of body development and homeostasis. In distant species and invertebrates, the foundations of both the neuroendocrine system and innate immunity were coexisting until now without any apparent problem. Some 400 millions years ago, in a relatively short period after agnathan fishes (e.g., hagfish and lamprey), adaptive immunity emerged in the first gnathostomes, cartilaginous fishes (e.g., shark and ray). Somatic recombination machinery characterizes adaptive immunity and is responsible for the random generation of the huge diversity of immune receptors able to recognize infectious antigens. The emergence of this novel form of immune defenses exerted a so potent pressure that structures and mechanisms developed along the paths of lymphocyte traffic to impose immunological self-tolerance, that is, the inability of the immune system to attack the host organism. Together with the generation of diversity and memory, self-tolerance constitutes a fundamental property of the immune system. The progressive rise in the level of immune diversity and complexity also explains why self-tolerance failures (i.e., organ-specific autoimmune diseases) were increasingly detected during evolution, the maximum being currently observed in the human species. The first thymus appeared in cartilaginous fishes (chondrichthyes), concomitantly with the emergence of rudimental forms of adaptive immunity. Though some forms of tolerance induction already takes place in primary hemopoietic sites (fetal liver and bone marrow), antigen-dependent B-cell tolerance is primarily due to an absence of T-cell help. Among all lymphoid structures, the thymus is the only organ specialized in the establishment of central self-tolerance. The thymus crucially stands at the crossroad between the immune and neuroendocrine systems. In this organ responsible for thymopoiesis—T-cell generation—(Kong et al., 1998), the neuroendocrine system regulates the process of T-cell differentiation from the very early stages. In addition, T lymphocytes undergo inside the thymus a complex educative process that establishes central T-cell self-tolerance of neuroendocrine principles (Geenen et al., 1992; Martens et al., 1996). Within the thymus, a confrontation permanently occurs between previously established neuroendocrine principles and a recent system equipped with recombination machinery promoting stochastic generation of response diversity. Contrary to a previous assumption, the thymus functions throughout life (Poulin et al., 1999; Geenen et al., 2003) and plays a fundamental role in the recovery of a competent T-cell repertoire after intensive chemotherapy or during highly active antiretroviral therapy (Mackall et al., 1995; Douek et al., 1998)