The vertebrate adaptive immune system has well defined functions in maintaining tolerance to self‐tissues. Suppression of autoreactive T cells is dependent on the regulatory cytokine transforming growth factor‐β (TGF‐β) and regulatory T (Treg) cells, a distinct T cell lineage specified by the transcription factor Foxp3. Although TGF‐β promotes thymic Treg (tTreg) cell development by repressing T cell clonal deletion and peripheral Treg cell differentiation by inducing Foxp3 expression, a recent study shows that TGF‐β suppresses autoreactive T cells (...) independent of Foxp3+ Treg cells. These findings imply that as an ancestral growth factor family member, TGF‐β may have been co‐opted as a T cell‐intrinsic mechanism of self‐tolerance control to assist the evolutionary transition of vertebrate adaptive immunity. Later, perhaps in placental mammals upon their acquisition of a TGF‐β regulatory element in the Foxp3 locus, the TGF‐β pathway is further engaged to induce peripheral Treg cell differentiation and expand the scope of T cell tolerance control to innocuous foreign antigens. (shrink)

Neddylation, a ubiquitylation‐like post‐translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1‐4 (Cullin‐RING ligases 1–4) and CRL5, respectively. While over‐activation of the neddylation‐CRLs axis occurs frequently in many human cancers, how neddylation‐CRLs regulate the function of (...) immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3‐Cre, and found that while the Ube2f‐Sag E2/E3 pair plays a minimal role, if any, the Ube2m‐Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

We analyse the effect of the regulatory T cells (Tregs) in the local control of the immune responses by T cells. We obtain an explicit formula for the level of antigenic stimulation of T cells as a function of the concentration of T cells and the parameters of the model. The relation between the concentration of the T cells and the antigenic stimulation of T cells is an hysteresis, that is unfold for some parameter values. We study the appearance of (...) autoimmunity from cross-reactivity between a pathogen and a self antigen or from bystander proliferation. We also study an asymmetry in the death rates. With this asymmetry we show that the antigenic stimulation of the Tregs is able to control locally the population size of Tregs. Other effects of this asymmetry are a faster immune response and an improvement in the simulations of the bystander proliferation. The rate of variation of the levels of antigenic stimulation determines if the outcome is an immune response or if Tregs are able to maintain control due to the presence of a transcritical bifurcation for some tuning between the antigenic stimuli of T cells and Tregs. This behavior is explained by the presence of a transcritical bifurcation. (shrink)

A large body of evidence on the activity of regulatory T (Treg) cells was gathered during the last decade, and a similar number of reviews and opinion papers attempted to integrate the experimental findings. The abundant literature clearly delineates an exciting area of research but also underlines some major controversies. A linear cause–result interpretation of experimental maneuvers often ignores the fact that the activity of Treg cells is orchestrated with the effector T (Teff) cells within an intricate network (...) of physiological immune homeostasis. Every modulation of the activity of the effector (cytotoxic) immune system revolves to affect the activity of regulatory (suppressive) cells through elaborate feedback loops of negative and positive regulation. The lack of IL‐2 production by innate Treg cells makes this cytokine a prime coupler of the effector and suppressive mechanisms. Here we attempt to integrate evidence that delineates the involvement of IL‐2 in primary and secondary feedback loops that regulate the activity of suppressive cells within the elaborate network of physiological immune homeostasis.©2007 Wiley Periodicals, Inc BioEssays 30:875–888, 2008. © 2008 Wiley Periodicals, Inc. (shrink)