The Role of the Thymus in Tolerance

Abstract

The thymus serves as the central organ of immunologic self-non-self discrimination. Thymocytes undergo both positive and negative selection resulting in T cells with a broad range of reactivity to foreign antigens but a lack of reactivity to self-antigens. The thymus is also the source of a subset of regulatory T cells that inhibit autoreactivity of T cell clones that may escape negative selection. As a result of these functions, the thymus has been shown to be essential for the induction of tolerance in many rodent and large animal models. Proper donor antigen presentation in the thymus following bone marrow, dendritic cell, or solid organ transplantation has been shown to induce tolerance to allografts. The molecular mechanisms of positive and negative selection and regulatory T cell development must be understood if a tolerance inducing therapeutic intervention is to be designed effectively. In this brief and selective review, we present some of the known information on T cell development and the role of the thymus on experimental models of transplant tolerance. We also cite some clinical attempts to induce tolerance to allografts using either pharmacologic or biologic interventions.

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

“…Indeed, an increase in the number of iNKT cells was observed in the chimeras ( Figure 9B). It was also considered that thymic DCs generate Tregs in thymus (46). We previously reported augmentation of pDCs, which can develop Tregs in the periphery (6,47,48), after lipo-aGC administration (8,10).…”

Lentiviral Vectors in Immunotherapy

“…Therefore, the immune system possesses several tolerogenic mechanisms in place to keep immunological homeostasis. As mentioned before, a key one is clonal deletion of auto-reactive T cells in the thymus [74]. However, there is a significant number of auto-reactive T cells that escape from clonal deletion.…”

“…However, there is a significant number of auto-reactive T cells that escape from clonal deletion. Many of them will differentiate towards natural Foxp3 CD4 regulatory T cells [74][75][76][77].…”

Dendritic Cells and Lentiviral Vectors: Mapping the Way to Successful Immuno Gene Therapy

“…Therefore, several tolerogenic mechanisms are constantly in place. One of the first mechanisms to be described is central tolerance, in which auto-reactive T cells are eliminated in the thymus by clonal deletion (Griesemer et al 2010). Although this mechanism is essential to eliminate most auto-reactive T cells, it can't explain the aetiology of autoimmune disorders in which self-antigens are clearly recognised.…”

“…Even though clonal deletion is efficient, it does not eliminate all auto-reactive T cells. Interestingly, many autoreactive T cells that survive clonal deletion further differentiate into natural Foxp3 + CD4 + Treg (Sakaguchi et al 2008;Griesemer et al 2010). These are strong and intrinsic immunosuppressive, and are part of the central tolerance.…”