Mechanisms of tolerance

Go to http://www.immunologicalreviews.com to watch interview with Guest Editor Jeffrey A. Bluestone Productive immune responses to foreign antigens are necessary to protect individuals against pathogens and allow survival in the external environment. The immune system has evolved to achieve efficient immunity against foreign antigens without mounting detrimental responses to self-antigens, thus preserving the integrity of the individual’s own tissues. This original paradigm of immune tolerance has developed to include not only the spontaneous absence of self-targeted responses in steady state or after an inflammatory response but also the pharmacologically induced state of non-responsiveness to foreign antigens deliberately introduced into individuals, such as organ grafts. Thus, tolerance can be defined as a lack of reactivity to self-antigens or foreign tissue antigens in an organ graft achieved without the need for long-term immunosuppression while retaining immune competence and reactivity to all other foreign antigens. From an evolutionary point-of-view, the critical importance of immune tolerance is illustrated by the multiple non-redundant mechanisms that are in place to establish this immunological state. Nevertheless, the challenges in attaining and maintaining this state are underlined by the prevalence of autoimmune diseases, the as-of-yet absence of routine tolerogenic therapies in organ transplantation, and the necessity to strike a balance between protecting the individual from autoimmunity while preserving responses against cancerous cells and foreign antigens. Central tolerance mechanisms eliminate many potentially autoreactive T cells in the thymus through negative selection and the preferred selection of thymocytes with high affinity to self toward the regulatory T-cell lineage. Yet, it is clear that potentially self-reactive thymocytes can pass this checkpoint and become a part of the peripheral T-cell repertoire. Peripheral tolerance mechanisms limit the activation of mature self-reactive T cells once they have exited the thymus. Autoreactive T cells may be tolerized by clonal deletion, anergy, or immunological ignorance. Their responses can be controlled by regulatory T cells (Tregs), B cells, or other regulatory leukocytes. It is notable that the concept of immunological tolerance was introduced more than 50 years ago by Medawar et al., well ahead of the characterization of basic features of immune responses as we know them now, such as the major histocompatibility complex (MHC)-restricted recognition of antigenic peptides by the T-cell receptor (TCR), the stages of thymic selection, or the existence of T-cell subsets and lineages, such as T-helper 1 (Th1), Th2, Th17 and Tregs. As narrated by Wood et al. in this issue (1), Medawar et al. observed that injection of allogeneic tissue into neonates led to immune tolerance to subsequent allografts (2). This led to the seminal concept that exposing the developing immune system to new antigens, including alloantigens, could induce specific immunological tolerance. The impact of this work has been tremendous and provided the basis to determine the mechanisms of tolerance and develop tolerogenic approaches in the clinic. Interestingly, plasticity of the immature immune system was noted as one of the keys to the success of the neonatal tolerance induction strategy in these early studies. The recent appreciation that there is also a certain degree of plasticity in mature T-cell subsets and dendritic cells (DCs) in the periphery suggests that the multi-level plasticity of the immune system is critical for the establishment of tolerance. Many other parameters have been proven to determine whether immune tolerance can be achieved (Fig. 1), including the route or location of antigen presentation (for example, oral administration of antigen or immunologically privileged sites favor tolerance), the source and form of antigen (dose, with or without adjuvant/inflammation, tissue antigen, etc.), the antigen-presenting cells (APCs) (cell types involved, e.g. B cells, monocytes/macrophages, DCs, non-professional APCs, etc., and their state of maturity and activation), cells responding to the stimulation (naive versus versus regulatory T cells, and of the etc.), the of T-cell versus the the and the plasticity of tolerance of T-cell of immunity can that tolerance is a in this of many of these parameters and their the induction or of immune tolerance. The individual of the and in of tolerance. this in to achieve a of tolerance. of immune tolerance. 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