Regulating the Regulators

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Science  14 Feb 2003:
Vol. 299, Issue 5609, pp. 1030-1031
DOI: 10.1126/science.1082031

Recently, there has been an explosion of interest among immunologists in a subset of T lymphocytes that prevent harmful immune pathology. These regulatory T cells (TR), most of which express the activation marker CD25, constitute a small number (5 to 10%) of the total population of CD4+ T lymphocytes present in healthy individuals. CD4+ TR cells prevent a number of immune-mediated diseases, including autoimmune disorders, transplant rejection, and inflammatory bowel disease (1). Recent studies including two papers in this issue, by Hori et al. (2) on page 1057 and Pasare and Medzhitov (3) on page 1033, are beginning to elucidate TR cell biology in more detail, particularly aspects of their differentiation and functional capabilities. These studies emphasize that TR lymphocytes do not act in isolation, but are themselves influenced by cells of the innate immune system. An equilibrium is thereby established that allows effective responses against dangerous microbes while minimizing immune pathology.

The identification of transcription factors that direct the differentiation of naïve CD4+ T cells into functionally distinct T helper 1 (TH1) and TH2 cells has transformed our understanding of the molecular basis of CD4+ effector T cell responses (4). The study by Hori et al. (2) identifies the forkhead/winged helix transcription factor Foxp3 as a master regulator that promotes TR cell differentiation. These investigators noted that both humans and mice with mutations in the Foxp3 gene developed a spectrum of autoimmune and inflammatory diseases similar to that seen in rodents lacking CD4+CD25+ TR cells. Assays of Foxp3 mRNA expression in normal mice showed that it is predominantly expressed by CD4+CD25+ TR cells and not by other populations of naïve or effector T cells. Using a retroviral transduction vector, the authors found that ectopic expression of Foxp3 converted naïve CD4+CD25- T cells into cells with the phenotypic and functional characteristics of TR cells. Importantly, the Foxp3-transduced T cells were able to inhibit autoimmune gastritis and inflammatory bowel disease in murine models in vivo.

In contrast to conventional CD4+ T lymphocytes, CD4+CD25+ TR cells can fully differentiate in the thymus (5). The Hori et al. study does not directly address the role of Foxp3 during the differentiation of TR cells in the thymus. However, additional studies indicate that CD4+CD25+ TR cells are absent in Foxp3-deficient mice, providing confirmation that Foxp3 acts as a master switch for TR cell development (6). These studies represent an important step toward unraveling the events that dictate TR cell lineage commitment. Further characterization of the molecular mechanisms involved should identify factors modulating TR cell development that then could be tailored for therapeutic purposes. But what induces Foxp3 expression in developing or naïve T cells in vivo? An attractive possibility is that Foxp3 expression is induced by specialized populations of antigen-presenting cells (APCs) (see the figure). In the thymus, development of TR cells requires antigen presentation by thymic epithelial cells (TECs) (5); in the periphery, similar signals may be provided by resting populations of dendritic cells (DCs).

Innate immune cells control TR cell development and activation.

The activation state of APCs determines the type and magnitude of the CD4+ T cell response. Resting APCs (including epithelial cells in the thymus) may promote the development of CD4+CD25+TR cells by inducing Foxp3 expression in CD4+ T cells. During infection by pathogens, recognition of microbial molecules by TLRs results in activation of APCs. The APCs then produce IL-6 and additional soluble factors that together override the suppressive effects of TR cells, allowing efficient generation of TE cells against the pathogen. The dynamic equilibrium between resting and activated APCs will also be influenced by the actions of both TR and TE cells.

Precisely how TR cell activity is regulated to allow effective immune responses toward pathogens without pathological anti-self reactivity has puzzled immunologists. Microbial infections are primarily detected by cells of the innate immune system, which use a variety of pattern recognition receptors to detect signature molecules expressed by pathogens. One of the most important families of innate immune receptors are the Toll-like receptors (TLRs). They recognize a variety of microbial products, such as bacterial cell wall components and prokaryotic DNA motifs (7). Recognition of microbial molecules by TLRs expressed on DCs triggers activation of DCs, leading to the initiation of an appropriate effector T (TE) cell response (see the figure). TLR-induced DC activation increases DC costimulation, which directly enhances the activation of TE cells.

In a ground-breaking study, Pasare and Medzhitov (3) now show that activation of TLR signaling in DCs also acts in a cell-extrinsic way to enhance TE cell responses by overcoming CD4+CD25+ TR cell suppression. This blockade of TR cell activity requires interleukin-6 (IL-6) secretion by activated DCs, although IL-6 alone is not sufficient because another TLR-induced factor is also needed. This hitherto overlooked function of IL-6 makes targeting of this cytokine an attractive candidate for treatment of inflammatory diseases, as has already been demonstrated for inflammatory bowel disease (8). Key questions include, what other factors act together with IL-6 and how do they override TR cell activity? With regard to the latter, the factors secreted by activated DCs appear to act on responder T cells, making them refractory to the inhibitory effects of TR cells. The crucial part played by IL-6 in overcoming TR cell activity in vivo was confirmed by the finding that efficient TE cell priming could be restored in IL-6-deficient mice by depletion of CD4+CD25+ TR cells (3). These results reinforce the instructive role of innate immune cells (DCs) on adaptive immune responses and demonstrate that for efficient TE cell activation, it is necessary to overcome dominant negative regulation by TR cells. On a cautionary note, recent studies suggest that pathogen recognition by innate immune receptors may not always be stimulatory; molecules derived from some bacterial pathogens can inhibit APC activation, resulting in suppression of immunity and an IL-10-dominated response (9, 10). Both IL-10 and nonactivated APCs may enhance the development of pathogen-specific TR cells, which arise in a number of different types of infection (9, 11, 12). Although such TR cells may contribute to pathogen persistence, they may also benefit the host by preventing harmful pathology mediated by excessive anti-pathogen immune responses.

The new findings encourage us to think about TR cells as an integral component of the immune response. These cells primarily appear to fine tune protective antimicrobial immunity in order to minimize harmful immune pathology. The decision of how to respond will still be primarily determined by interactions between pathogens and cells of the innate immune system, but the actions of both TR cells and TE cells will feed back into this dynamic equilibrium to regulate subsequent immune responses. Future studies on the factors controlling the development and activation of TR cells should enable us to shift the equilibrium either toward TR cell activity (to treat autoimmune diseases and to enhance survival of organ transplants), or away from TR cell activity (to boost vaccination and tumor rejection).


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