Generation of a Novel T Cell Specific Interleukin-1 Receptor Type 1 Conditional Knock Out Mouse Reveals Intrinsic Defects in Survival, Expansion and Cytokine Production of CD4 T Cells

Abstract

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.

Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin

“…Again, both WT and IL-1R-deficient cells proliferated robustly in response to infection (Fig S5b). As a third approach, we performed adoptive transfer experiments using BM from mice lacking Il1r1 specifically in TCRαβ + cells (37). Again, TCRαβ + cells proliferated following OPC (Fig S5c), indicating that IL-1 signals occur in both hematopoietic and non-hematopoietic cells.…”

“…Act1 −/− mice were from U. Siebenlist (NIH) (51). CD4 CRE Il1r1 fl/fl mice were described (37). Il17a Cre Rosa26 eYFP fate reporters (17) and other mice were from JAX (except as noted for Taconic Farms, Albany NY) and housed at the University of Pittsburgh for at least 7 d prior to experimentation.…”

IL ‐1 signaling is critical for expansion but not generation of autoreactive GM ‐ CSF + Th17 cells

“…These mice developed normally and did not display abnormalities in the immune system when kept under SPF conditions. However, CD4 T cells isolated from mutant mice failed to proliferate in response to IL‐1β administration in vitro (Mufazalov et al , ). Previously, it was reported that IL‐1R1 fully deficient mice show an impaired CD4 T‐cell‐mediated antigen response and that these mice are resistant to induction of EAE (Matsuki et al , ; Sutton et al , ; Chung et al , ).…”

“…The Il1r1 fl/fl mouse strain with exon 5 of Il1r1 gene flanked by loxP sites was crossed to Cd4‐Cre and CMV‐Cre mice resulting in IL‐1R1 ΔT and IL‐1R1 −/− mouse strains, respectively (Mufazalov et al , ). Rag1 −/− mice were obtained from in‐house breeding.…”

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

“…Collectively, these studies suggest the possibility that hematopoietic non-T H cells, radioresistant microglia, and/or radioresistant non-hematopoietic cells all may respond to IL-1β to enhance neuroinflammation during EAE. Future studies using Il1r1 fl/fl mice (34, 86–88) crossed to additional Cre-expressing strains should be useful to dissect the roles of the aforementioned cell types.…”