In vivodynamics of antigen-specific regulatory T cells not predicted from behaviorin vitro

Abstract

Dominant mechanisms of tolerance control the autoimmune potential of self-reactive T cells in healthy individuals and animals (reviewed in refs. 1-3). Insights into the regulation of immune responses by regulatory T cells have been mostly obtained with polyclonal populations of regulatory T cells for which the role of specific antigen has been largely obscure. The impact of self-antigen on the shaping of the regulatory T cell pool came more into focus when it was observed that the coexpression of a transgenic class II MHC restricted T cell receptor (TCR) and its agonist ligand resulted in the generation of antigen-specific regulatory T cells (4). Subsequent experiments in that system confirmed the notion that thymic epithelium can have a decisive role in the formation of such cells by demonstrating that the expression of an agonist ligand on radioresistant tissue (5) and on transplanted thymic epithelium (6) was a very effective means of generating regulatory T cells, whereas the mode of generation of polyclonal regulatory T cells in normal mice still needs to be elucidated.A subset of CD4 ϩ T cells expressing the interleukin-2 (IL-2) receptor ␣-chain (CD25) recently became a major focus of interest. These CD4 ϩ CD25 ϩ T cells were first shown by Sakaguchi and colleagues to control autoreactive T cells in vivo (7). Several characteristics of these cells have emerged from in vitro studies (reviewed in ref. 8) resulting in the notion that regulatory T cells are anergic in terms of proliferation and suppress other cells by direct cell contact, which requires neither IL-10 nor transforming growth factor-␤ and which results in the inability of suppressed CD4 ϩ T cells to produce IL-2 (9-11). However, it is unclear at present how far these observations in vitro are in fact a reflection of the properties of CD4 ϩ CD25 ϩ T cells in vivo. In some experimental systems of immune regulation by CD4 ϩ CD25 ϩ T cells in vivo, it was found that soluble factors such as IL-4, IL-10, and transforming growth factor-␤ do contribute to the prevention of autoimmunity, with the role of these factors var ying between different models (12-14). Polyclonal CD25 ϩ CD4 ϩ T cells proliferate and expand when they are transferred into rag Ϫ/Ϫ or IL-2 receptor ␤-deficient mice (15-17), indicating that their anergic state can be reversed under certain nonphysiological conditions. Notably, it is under exactly these lymphopenic conditions that the regulatory function of CD25 ϩ CD4 ϩ T cells has been studied in the majority of the currently available models, at least suggesting that proliferation and suppressive function by regulatory T cells may not be mutually exclusive. A major experimental drawback of lymphopenic models of immune regulation, however, is that they provide no information on antigen-induced proliferation as observed in nonlymphopenic mice.The present study was initiated to establish an in vivo system of antigen-specific immune regulation that is as physiological as possible to characterize the behavior of CD25 ϩ CD4 ϩ regulatory T ...

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

“…Thus, Treg competition for IL-2 is boosted by the positive-feedback loop of IL-2 uptake and CD25 up-regulation. The same inverse regulation of CD25 expression on Treg versus responder T cells has been observed in vivo [12,17] upon adoptive co-transfer of Treg and responder T cells.…”

“…The constitutive expression of all three chains of the high-affinity IL-2 receptor enables Treg to take up IL-2 without previous activation [15,26]. Using the CD25 expression level, which is positively regulated by IL-2 [32,33], as an indicator for IL-2 uptake, it has been demonstrated in vitro and in vivo that competition for IL-2 indeed occurs [12,15,17]. During co-culture of Treg with responder T cells, Treg up-regulate CD25, whereas induction of CD25 expression on responder T cells is suppressed.…”

“…Indeed, to acquire the capacity to produce IL-10, Treg had to be activated in vitro via their TCR in the presence of IL-2 for at least 2-3 days [15]. Furthermore, Treg isolated from sites of ongoing immune responses in vivo are able to produce high amounts of IL-10 upon restimulation ex vivo [7,11,12,47].…”

“…Also, Treg isolated from secondary lymphoid organs of normal mice do not produce IL-10 or TGF-b upon re-stimulation. In contrast, there is evidence that IL-10 and TGF-b may be relevant mediators of suppression in vivo [6][7][8][9][10][11] and Treg isolated from sites of active immune reactions are able to produce high amounts of IL-10 upon re-stimulation [7,11,12]. Recent data indicate that IL-2 is critical for the activation of Treg effector function, such as production of IL-10.…”

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

“…The predominant accumulation of effector/effector memory Treg subset at the tumor site may constitute a crucial factor hindering antitumor immunity, since effector/memory Treg have enhanced suppressive activity and higher proliferation capacity. 23 …”