Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23

SummaryInterleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways

A study of murine T lymphocyte responses to Streptococcus pyogenes

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN026636 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Spectroscopic Investigation of a Metal Metal Bonded Fe6 Single Molecule Magnet with an Isolated S 19 2 Giant Spin Ground State

The metal metal bonded molecule [Bu4N][ HL 2Fe6 dmf 2] Fe6 was previously shown to possess a thermally isolated spin S 19 2 ground state and found to exhibit slow magnetization relaxation below a blocking temperature of amp; 8764;5 K [J. Am. Chem. Soc.2015, 137, 13949 13956]. Here, we present a comprehensive spectroscopic investigation of this unique single molecule magnet SMM , combining ultrawideband field swept high field electron paramagnetic resonance EPR with frequency domain Fourier transform terahertz EPR to accurately quantify the spin Hamiltonian parameters of Fe6. Of particular importance is the near absence of a 4th order axial zero field splitting term, which is known to arise because of quantum mechanical mixing of spin states on account of the relatively weak spin spin superexchange interactions in traditional polynuclear SMMs such as the celebrated Mn12 acetate. The combined high resolution measurements on both powder samples and an oriented single crystal provide a quantitative measure of the isolated nature of the spin ground state in the Fe6 molecule, as well as additional microscopic insights into factors that govern the quantum tunneling of its magnetization. This work suggests strategies for improving the performance of polynuclear SMMs featuring direct metal metal bonds and strong ferromagnetic spin spin exchange interaction

Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis

Reestablishing self-tolerance in autoimmunity is thought to depend on self-reactive regulatory T cells (Tregs). Exploiting these antigen-specific regulators is hampered by the obscure nature of disease-relevant autoantigens. We have uncovered potent disease-suppressive Tregs recognizing Heat Shock Protein (Hsp) 70 self-antigens, enabling selective activity in inflamed tissues. Hsp70 is a major contributor to the MHC class II ligandome. Here we show that a conserved Hsp70 epitope (B29) is present in murine MHC class II and that upon transfer, B29-induced CD4(+)CD25(+)Foxp3(+) T cells suppress established proteoglycan-induced arthritis in mice. These self-antigen–specific Tregs were activated in vivo, and when using Lymphocyte Activation Gene-3 as a selection marker, as few as 4,000 cells sufficed. Furthermore, depletion of transferred Tregs abrogated disease suppression. Transferred cells exhibited a stable phenotype and were found in joints and draining lymph nodes up to 2 mo after transfer. Given that (i) B29 administration by itself suppressed disease, (ii) our findings were made with wild-type (T-cell receptor nontransgenic) Tregs, and (iii) the B29 human homolog is presented by HLA class II, we are nearing translation of antigen-specific Treg activation as a promising intervention for chronic inflammatory diseases