Induction of peripheral CD4⁺ T‐cell tolerance and CD8⁺ T‐cell cross‐tolerance by dendritic cells

Abstract

DC can present and cross-present self-antigens to autoreactive CD4 1 and CD8 1 T cells, respectively, and incapacitate them by inducing anergy, deletion or converting them into Treg. In this review, we summarize the recent progress in immune tolerance research, which has been achieved by employing antigen-and TCR-transgenic mice. We cover the numerous discoveries that have furthered our knowledge of the DC subsets and maturation pathways involved in tolerance; the signals, such as CD70, TGF-b, B7-H1/PD-L1, which dictate the decision between immunity and tolerance; and the in vivo role of DC in the maintenance of CD4 1 T-cell tolerance and CD8 1 T-cell cross-tolerance.Key words: Cross-presentation/priming . DC . T cells . Tolerance IntroductionTolerance of T cells to self-antigens is controlled at several levels. Thymic selection results in the release of high-affinity T cells specific for non-self-antigens, low-affinity T cells specific for self-antigens, and so-called natural Treg (nTreg) with an intermediate affinity to both self-and non-self-antigens into the circulation. In the steady-state, the self-reactive T cells may then interact with tissue cells or professional APC that present self-antigens both on MHC class I and II molecules. In the absence of infection or inflammation naive T cells will be either deleted, anergized, converted into adaptive CD4 1 CD251 Foxp3 1 Treg (aTreg) or develop into CD4 1 Foxp3 À IL-10-producing Treg (Tr1) [1,2]. The specific outcome is directed not only by the DC subset involved, the activation state of the DC, and the cytokine milieu of the anatomical location, but also by T-cell-intrinsic factors such as the TCR avidity. In addition, the nTreg, derived from the thymus, are continuously re-activated in LN to control self-reactive effector T cells [3]. The critical role for DC in the maintenance of CD4 1 T-cell self-tolerance has been summarized before [4] and has been further highlighted recently by conditional ablation of DC in mice [5][6][7]. Here, we review the recent findings relating to the mechanisms of DC presentation and cross-presentation of self-antigens in the maintenance of CD4 1 T-cell tolerance and CD8 1 T-cell cross-tolerance obtained using transgenic technology to visualize the otherwise very small repertoires of self-antigen-specific CD4 1 and CD8 1 T cells. This review will focus on the conventional (non-plasmacytoid) DC, referred to herein as DC.Antigen transport pathways for CD4 1 T-cell toleranceinduction in the draining LNThe immune system needs to be tolerized against self-antigens, including soluble and tissue-associated antigens, obtained for example from apoptotic cells [8]. LN-resident DC can capture soluble antigens from the reticular conduit system that originates from the upstream afferent lymphatics [9,10] Factors involved in the initiation, guidance and function of ssmDC In contrast to the factors guiding DC migration for T-cell priming, much less is known about the factors that control the mobilization of ssmDC. Only the requirement of CCR7 ...

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…1,2 In peripheral tissues, immature DCs sense the microenvironment and after their encounter with inflammatory stimuli or pathogens, DCs are activated; a process that is accompanied by several physiological changes and that ends with the maturation of DCs. [3][4][5] Once initiated the process of DCs maturation, the expression of CD80, CD86 and MHC class II molecules increases.…”

“…[3][4][5] Once initiated the process of DCs maturation, the expression of CD80, CD86 and MHC class II molecules increases. [1][2][3][4] The DCs migrate to the draining lymph nodes, as a result of the up-regulation of CCR7, which renders them responsive to CCL19 and CCL21 chemokines that direct their migration to the T-cell areas of lymph nodes. 6 Finally, the mature DCs present the antigen to naive CD4 + and CD8 + T lymphocytes.…”

“…12 Leukotriene C 4 (LTC 4 ), a member of the cysteinyl leukotriene family (CysLT), is a potent pro-inflammatory lipid mediator, produced by inflammatory cells such as mast cells, eosinophils, basophils and macrophages. 13,14 It is a potent spasmogen and vasoconstrictor, promotes mucus secretion, and together with histamine is a known immunomodulatory agent of allergic and inflammatory Carolina Alvarez, 1 María M. Amaral, 1 Cecilia Langellotti 2 and Mó nica Vermeulen 1 1 …”

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

“…These interactions are thought to prevent activation of these self-reactive T cells and consequently reinforce peripheral tolerance by means of the inhibition/ deletion of autoreactive T cells that could have escaped negative selection (Gardner, Devoss et al 2008). In addition, other peripheral mechanisms mediated by DCs can also contribute to tolerance, including induction of T cell anergy, deletion or alternatively induction of antigen-specifi c T regs (Lutz and Kurts 2009).…”

Dendritic cells in tolerance induction for the treatment of autoimmune diseases

“…Indeed, targeting of immature DC in vivo using a monoclonal antibody to DEC205 (a receptor for antigen uptake expressed by mouse lymph node DC) engineered to express a model antigen (OVA) induces tolerance to the model antigen [8]; however, it has become increasingly clear that the picture may be somewhat more complex, as supported by data showing that semimature or differently mature DC can also induce tolerance [9]. The mechanisms underlying DC tolerogenic function have been recently summarized elsewhere and will therefore not be discussed in this Viewpoint [10].…”