Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus

CD4 + CD25 + regulatory T cells control CD8 + T-cell effector differentiation by modulating IL-2 homeostasis

“…Recent studies have shown that both Treg and CD8 + T cells are exquisitely sensitive to modulation of IL-2 homoeostasis in vivo (15)(16)(17). Emerging evidence implicates alterations in IL-2 homeostasis in development of a range of autoinflammatory responses (18)(19)(20). Given the importance of CD8 T-cell responses in tumor clearance and autoimmunity, we investigated the interrelationship of IL-2, Treg, and CD8 + T-cell effector differentiation.…”

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

“…Besides reconstitution of the Treg population by adoptive transfer, potential treatment methods to achieve an in vivo expansion of endogenous Treg and a normalization of the ratio between Treg and Teff, might be as diverse as the initial reasons for the deficiency in the Treg population. Accordingly, it has been shown that administration of rIL-2 promotes the proliferation of endogenous Treg and delays the progression of established disease, most likely by re-establishing the homeostatic balance of Treg and effector T cells [87]. Supporting evidence from earlier studies also indicates that tolerance induction by injecting various tolerogenic peptides [91,115,123], anti-thymocyte globulin agents [95], or oral administration of anti-CD3 antibodies [97], are all associated with in vivo Treg expansion.…”

“…Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90]. Again, alternative findings demonstrating lupus Treg being functionally normal [49,50,62,67,85], or at least normal in majority of patients tested [48,64], or even enhanced in some way [68,80,87] added further confusion as well as interest to the matter. Upon a closer examination, these seemingly discrepant findings can in fact be logically explained.…”

“…We have previously demonstrated that, in two unrelated lupus mouse models, IL-2 deficiency is responsible for an early and progressive defect in T cell proliferation, which could be restored b y ex og en ou s I L -2 [ 7 ] . Th e c y t ok in e w a s in d e e d l a t er f ou n d to b e a b le t o r e s t or e Tr eg expansion and functions, both in vitro and in vivo, in the lupus mice [68,87]. In other words, under normal physiological conditions, the Treg-mediated suppressive action has to be 'endorsed' by their 'target cells' too.…”

Cytokines and Systemic Lupus Erythematosus

“…It was initially identified as a potent T cell growth factor, however, more recent data strongly indicate that IL-2 is essential for immune tolerance (Humrich et al, 2010). IL-2 constitutes a key element in the maintenance of the homeostasis between a proliferative immune response and the induction of tolerance, which supports the involvement of this cytokine in diverse autoimmunity disorders, such as SLE (Sharma et al, 2011).…”