OF MICE AND MEN : AN HISTORICAL PERSPECTIVE ON Tregs 1 . 1 Characterization of Suppressor T Cells

Regulatory T cells (Tregs) are critical to maintain the homeostasis of the organism, i.e., to prevent (excessive) inflammatory reactions against self and nonself. Data in the literature suggest that a variety of suppressive mechanisms exist that may act selectively depending on the tissue environment. An interesting question is whether dendritic cells (DCs), which are involved in immunity and tolerance, are targets of Tregs. We review herein some experimental evidence indicating that some suppressive mechanisms involve DCs, altering their function and inducing an immune control at the very first step of the immune response. Progress in Molecular Biology and Translational Science, Volume 136 # 2015 Elsevier Inc. ISSN 1877-1173 All rights reserved. http://dx.doi. org/10.1016/bs.pmbts. 2015.08. 003 131 Dendritic cells (DCs), discovered by Steinman in 1973, play opposite roles in the immune system: they have the unique capacity to present antigens in an immunogenic or tolerogenic form and therefore control the switch between immunity and tolerance. The stimulatory capacity of DCs has been amply demonstrated in the years that followed their discovery. They were described as the most potent stimulators of the primary mixed leukocyte reaction in mice. They were considered as sentinels of the immune system, able to detect “danger signals” in the periphery and to activate T lymphocytes in lymphoid organs. Their unique capacity to activate optimally naı̈ve T cells correlated with a specialization of function over time, i.e., they shift from an antigen-presenting mode to a T cell sensitizing mode while migrating to the T cell zones of lymphoid organs. During this process called “maturation,” DCs upregulated major histocompatibility complex (MHC) and costimulatory molecule expression and became able to provide both signals to T cells. This simple view of DCs as inducers of immunity was challenged in 2001 whenHawiger and colleagues used a monoclonal antibody to a DC-restricted endocytic receptor to target an antigen toDCs in vivo. Unexpectedly, antigenspecific T cells were initially activated but could not be reactivated when the same antigen was delivered in an immunogenic form. In contrast, coadministration of DC-targeted antigen and anti-CD40 agonistic antibody resulted in prolongedT cell activation. The authors suggested that the primary role of DCsmay be tomaintain tolerance in the steady state. Subsequent studies confirmed the existence of DCs displaying tolerogenic properties, which appeared critical to maintain immune homeostasis, as constitutively DC-depletedmice or mice in which DCs presented a defect in uptake of apoptotic cellular antigen-developed autoimmunity. The molecular mechanisms involved remained elusive and could imply the stage of maturation, the nature of the DC subset, the secretion of inhibitory cytokines, etc. In addition to DCs, regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance and immune homeostasis. Their importance is best evidenced by the lethal autoimmune syndrome in mice or human lacking a functional Treg population. Although Tregs were initially believed to control immune responses to self, there is now clear evidence that they not only prevent autoimmunity but also keep in check responses to foreign antigens, such as microbial components, thereby preventing excessive inflammatory responses. The critical role of DCs in the control of immunity versus tolerance and the close interaction between Tregs and DCs suggested a reciprocal 132 Maxime Dhainaut and Muriel Moser