RAGE Ligation Affects T Cell Activation and Controls T Cell Differentiation

Abstract

The pattern recognition receptor, RAGE, has been shown to be involved in adaptive immune responses but its role on the components of these responses is not well understood. We have studied the effects of a small molecule inhibitor of RAGE and the deletion of the receptor (RAGE−/− mice) on T cell responses involved in autoimmunity and allograft rejection. Syngeneic islet graft and islet allograft rejection was reduced in NOD and B6 mice treated with TTP488, a small molecule RAGE inhibitor (p < 0.001). RAGE−/− mice with streptozotocin-induced diabetes showed delayed rejection of islet allografts compared with wild type (WT) mice (p < 0.02). This response in vivo correlated with reduced proliferative responses of RAGE−/− T cells in MLRs and in WT T cells cultured with TTP488. Overall T cell proliferation following activation with anti-CD3 and anti-CD28 mAbs were similar in RAGE−/− and WT cells, but RAGE−/− T cells did not respond to costimulation with anti-CD28 mAb. Furthermore, culture supernatants from cultures with anti-CD3 and anti-CD28 mAbs showed higher levels of IL-10, IL-5, and TNF-α with RAGE−/− compared with WT T cells, and WT T cells showed reduced production of IFN-γ in the presence of TTP488, suggesting that RAGE may be important in the differentiation of T cell subjects. Indeed, by real-time PCR, we found higher levels of RAGE mRNA expression on clonal T cells activated under Th1 differentiating conditions. We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1+ T cells.

Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses

“…Thus, the increased levels of CHI3L3 together with high levels of several Th2-related cytokines in wild-type mice strongly suggests that urethane is inducing the archetypical Th2-polarized inflammatory response which operates under protumoral stimuli (44). In contrast, the absence of increased levels of CHI3L3 in Mmp1a Ϫ/Ϫ mice together with the presence of high levels of RAGE and its ligand S100A8, which are Th1 markers (33,34), as well as high levels of IFN-␥ and other antitumor cytokines such IL-1␣ and IL-2, is consistent with the possibility that Mmp1a deficiency hampers the Th2 response triggered by carcinogen injection in Mmp1a Ϫ/Ϫ mice. Moreover, further studies showed that mice that developed higher number of lung tumors did not display the Th1 cytokine profile observed in their mutant counterparts.…”

“…Carcinogenesis-Because the high levels of CHI3L3 in wildtype mice could be indicative of a Th2 protumoral inflammatory response (32,33), and the increased levels of RAGE and its ligand S100A8 in mutant mice could point to the occurrence of a Th1 anti-tumoral response (33,34), we next evaluated the levels of Th1 and Th2 cytokines in lungs from wild-type and Mmp1a knock-out mice. To this aim, a total of 14 different mouse cytokines were simultaneously analyzed by flow cytometry.…”

Critical role of RAGE and HMGB1 in inflammatory heart disease

“…It has also previously been shown that RAGE deficiency affected maturation and migration of dendritic cells and their cross-talk with natural killer (NK) cells, which is pivotal for sustaining innate immunity and initiating a subsequent adaptive immune response (40,41). In addition, RAGE deficiency has been linked to drastically reduced T-cell activation and differentiation, leading to suppressed B-cell response (40,42).…”

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Furthermore, clonal populations of Rage −/− mice-derived T cells adoptively Monocytes and macrophages seem to be central to the initiation and propagation of RAGE-dependent inflammation transferred into wild-type recipients showed reduced responses [82]. Syngeneic islet graft and islet allograft rejection were reduced in diabetic mice treated with small molecule RAGE inhibitors and in diabetic Rage −/− mice [80], suggesting a close link between RAGE and the pathogenesis of type 1 diabetes [15]. It is not known why RAGE participates in some, but not all adaptive immune responses.…”

“…Other studies, however, indicate a direct effect of RAGE on mobilisation of dendritic cells [79] and T cell migration, localisation, activation and differentiation [35,75,80], whereas HMGB1 signalling through RAGE seems to be required for clonal expansion, survival and functional polarisation of naive T cells [81]. Furthermore, clonal populations of Rage −/− mice-derived T cells adoptively Monocytes and macrophages seem to be central to the initiation and propagation of RAGE-dependent inflammation transferred into wild-type recipients showed reduced responses [82].…”