Interleukin-1 (IL-1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which IL-1 is involved in the generation of pathogenic T cells and in disease development remains largely unknown. We found that following EAE induction, pertussis toxin administration leads to IL-1 receptor type 1 (IL-1R1)-dependent IL-1b expression by myeloid cells in the draining lymph nodes. This myeloid-derived IL-1b did not vitally contribute to the generation and plasticity of Th17 cells, but rather promoted the expansion of a GM-CSF + Th17 cell subset, thereby enhancing its encephalitogenic potential. Lack of expansion of GM-CSF-producing Th17 cells led to ameliorated disease in mice deficient for IL-1R1 specifically in T cells. Importantly, pathogenicity of IL-1R1-deficient T cells was fully restored by IL-23 polarization and expansion in vitro. Therefore, our data demonstrate that IL-1 functions as a mitogenic mediator of encephalitogenic Th17 cells rather than qualitative inducer of their generation.
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. Despite an apparent simplicity in IL-1 signaling activation, multiple negative regulators have been identified. The decoy receptor IL-1R2 (also known as CD121b) can suppress IL-1 maturation, sequester its active forms or hinder the signaling complex assembly. IL-1R2 is differentially expressed among numerous cell types and displays cis- and trans- modes of action. In this review, we link different forms of IL-1R2 (membrane-bound (mIL-1R2), secreted (sIL-1R2), shedded (shIL-1R2), cytoplasmic, and intracellular domain (IL-1R2) restricted) with their ability to interfere with IL-1, thereby regulating immune responses. We also discuss the intriguing possible function of IL-1R2 as a transcriptional regulator. Finally, we summarize the known impact of IL-1R2 in disease pathogenesis and discuss its potential role in treatment of inflammatory conditions.
The vast majority of Foxp3 + regulatory T cells (Tregs) are generated in the thymus, and several factors such as cytokines and unique thymic antigen-presenting cells are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3 + Tregs within the thymus, characterised by the expression of IL-1R2, a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of thymocytes from Foxp3 hCD2 xRAG1 GFP reporter mice revealed that IL-1R2 + Tregs are mainly RAG1 GFPand CCR6 + CCR7-, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and display an activated phenotype. In the spleen, the majority of IL-1R2 + Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin of these Tregs. Interestingly, among all tissues studied the highest frequency of IL-1R2 + Tregs was observed in the thymus, indicating a preferential recruitment of this Treg subset back to the thymus. Using fetal thymic organ cultures (FTOCs), we could demonstrate that increased concentrations of exogenous IL-1 cause a block of intrathymic Treg development, resulting in decreased frequencies of CD25 + Foxp3 + tTregs and an accumulation of CD25 + Foxp3-Treg precursors. Interestingly, addition of IL-1R2 + , but not IL-1R2-Tregs to reaggregated thymic organ cultures (RTOCs) could abrogate this IL-1-mediated block, demonstrating that recirculating IL-1R2 + Tregs can quench IL-1 signals in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.
Interleukin-1 (IL-1) plays a crucial role in numerous inflammatory diseases via action on its only known signaling IL-1 receptor type 1 (IL-1R1). To investigate the role of IL-1 signaling in selected cell types, we generated a new mouse strain in which exon 5 of the Il1r1 gene is flanked by loxP sites. Crossing of these mice with CD4-Cre transgenic mice resulted in IL-1R1 loss of function specifically in T cells. These mice, termed IL-1R1ΔT, displayed normal development under steady state conditions. Importantly, isolated CD4 positive T cells retained their capacity to differentiate toward Th1 or Th17 cell lineages in vitro, and strongly proliferated in cultures supplemented with either anti-CD3/CD28 or Concanavalin A, but, as predicted, were completely unresponsive to IL-1β administration. Furthermore, IL-1R1ΔT mice were protected from gut inflammation in the anti-CD3 treatment model, due to dramatically reduced frequencies and absolute numbers of IL-17A and interferon (IFN)-γ producing cells. Taken together, our data shows the necessity of intact IL-1 signaling for survival and expansion of CD4 T cells that were developed in an otherwise IL-1 sufficient environment.
Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2–6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific β2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of β2 integrins in vivo.
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