Enhanced GITR/GITRL interactions augment IL‐27 expression and induce IL‐10‐producing Tr‐1 like cells

Abstract

The glucocorticoid-induced TNFR-related (GITR) protein is a coactivating receptor that is constitutively expressed on Treg cells and induced on activated T cells. To better understand the role of long-term GITR signaling, we generated a mouse that constitutively expresses GITR ligand (GITRL) on APCs that mimics the physiological distribution of GITRL in vivo. Despite a five-fold expansion of the Treg-cell pool, there is increased activation and depletion of naive T cells in the transgenic (Tg) mice, suggesting that the increased number of Treg cells cannot fully suppress T-cell activation. Interestingly, GITRL Tg mice have multiorgan lymphocytic infiltrates yet display no overt autoimmunity, indicating the existence of a compensatory immunoregulatory mechanism(s). In the spleens and tissue infiltrates of GITRL Tg mice, we found increased numbers of Foxp3glucocorticoid-induced TNFR-related (GITR) receptor and its ligand, GITRL [2]. In T cells, GITR is constitutively expressed at a high basal level on CD25 + Foxp3 + Treg cells and is induced rapidly, yet transiently, on activated CD4 + and CD8 + conventional effector T (Teff) cells. Its ligation by GITRL exerts a costimulatory signal that triggers TCR-dependent proliferation and the expansion of Treg and Teff cells [3].GITRL is constitutively present on resting APCs, and its expression is downregulated by triggering the BCR, CD40, or several TLRs [4,5] Eur. J. Immunol. 2012. 42: 1393-1404 induced by GITR/GITRL interactions modulate both innate and adaptive immune responses [5,6], however the functional outcome of such interaction is largely dependent on each specific model tested and is often controversial. Reduced inflammatory responses to acute and chronic lung inflammation were observed in GITR −/− mice compared with GITR +/+ mice, indicating a proinflammatory role of GITR in tissue inflammation [7]. Studies using agonist anti-GITR Ab or GITRL-Fc as an adjuvant further demonstrated GITR enhancement of both humoral and cellular immunity [8][9][10] To better understand the in vivo role of T-cell signaling through GITR, especially under long-term GITR stimulation, we generated a mouse that constitutively expresses GITRL on MHC class II + cells. In contrast to a previously reported B cell-specific GITRL transgenic (Tg) mouse that has a balanced proliferation of both Teff and Treg compartments with an intact naive (Tn) population [11], we found excessive T-cell activation and multiorgan lymphocytic infiltrations in our Tg model. However, we also discovered that long-term GITR signaling could generate additional/alternative immunosuppressive cells, including the differentiation of Tr-1like cells by increased levels of IL-27, which may control peripheral tissue inflammation through the production of the anti-inflammatory cytokine IL-10. Results Expanded Treg cells in GITRL Tg mice are unable to control constant naïve T cell activation in vivoIn GITRL Tg mouse, 80∼90% of cells that constitutively express MHC class II molecules, including the majority of B cells, DCs, ...

Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted

“…4). Consistent with these data, we observed an increase of both cCD4 + T and Treg cells in the GITRL transgenic mice, accompanied by multiorgan lymphocytic infiltration without any sign of autoimmune disease (27,28), which suggests that the GITR/GITRL interaction regulates the balance between regulatory and effector CD4 + T cells. Our data also indicate that authentic GITR signaling has a dual effect on immune responses-a stimulatory effect on conventional T cells and an inhibitory effect via Treg cells.…”

GITR+ regulatory T cells in the treatment of autoimmune diseases

“…In wild type mice, 1% of CD4 + T cells in the spleen are FoxP3 − IL-10 + independent of age, whereas in transgenic mice with antigen-presenting cells that constitutively express GITRL, the FoxP3 − IL-10 + subset is 1% in 2 week-old mice and increases to 6%-7% in 12 week-old mice, suggesting that chronic GITR/ GITRL signaling induces the generation/expansion of FoxP3 − IL-10-producing Tr1-like cells [57]. The addition of a neutralizing anti-IL-10 monoclonal antibody (mAb) restored T-cell proliferation in suppression assays, indicating that suppression by the Tr1-like cells was mediated by IL-10.…”

“…These cells express FoxP3 (at levels lower than CD25 high cells), CTLA-4, IL-10, and TGF-β, and are CD45RA − . Thus, CD4 + CD25 low/− GITR + cells are similar to human Tr1 clones [78] and Foxp3 − IL-10-producing Tr1-like cells expanded in GITRL − transgenic mice [57]. Recently, Tr1 precursor cells were detected in peripheral blood lymphocytes and characterized as CD4 + LAG-3 + CD49b + [79].…”

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

“…30,[32][33][34] It has also been showed that the long-term interactions of GITR/GITRL signaling boosted Tr1-cell differentiation and expansion in mice in vivo. 35 Zohar et al believed that chemokine (C-X-C motif) ligand 11/chemokine receptor 3 (CXCL11/CXCR3) interaction may induce transformation of CD4…”