[CITATION][C] Mechanisms of tolerance

JA Bluestone - Immunological reviews, 2011 - Wiley Online Library
Immunological reviews, 2011Wiley Online Library
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 …
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 antigenpresenting cells (APCs)(cell types involved, eg B cells, monocytes⁄ macrophages, DCs, non-professional APCs, etc., and their state of maturity and activation), cells responding to the stimulation (naive versus memory, effector versus regulatory T cells, size and avidity of the repertoire, etc.), cytokine milieu, the role of T-cell intrinsic signals versus extrinsic regulation, the genetic background, the environmental milieu, and the plasticity of tolerance (plasticity of T-cell subsets, role of innate immunity which can break tolerance, acknowledgment that tolerance itself is a dynamic state). Reviews in this volume of Immunological Reviews discuss many of these parameters and their influence on the induction or maintenance of immune tolerance. The individual reviews provide in-depth discussion of the data and contributions made in each area of tolerance. In this introduction, I summarize key elements in each review to achieve a coherent overall picture of tolerance.
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