CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance

Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation

Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3−/−) were generated. Gab2/3−/− mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3−/− hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3−/− mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis

Phospholipase Cγ1 is essential for T cell development, activation, and tolerance

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance

Critical role for Gimap5 in the survival of mouse hematopoietic stem and progenitor cells

HSCs lacking the guanosine nucleotide-binding protein Gimap5, which stabilizes expression of the Mcl-1 Bcl2 family protein, exhibit impaired survival and long-term repopulation capacity

LEAP-2017: Comparison of the Type-B Numerical Simulations with Centrifuge Test Results

This paper presents comparisons of 11 sets of Type-B numerical simulations with the results of a selected set of centrifuge tests conducted in the LEAP-2017 project. Time histories of accelerations, excess pore water pressures, and lateral displacement of the ground surface are compared to the results of nine centrifuge tests. A number of numerical simulations showed trends similar to those observed in the experiments. While achieving a close match to all measured responses (accelerations, pore pressures, and displacements) is quite challenging, the numerical simulations show promising capabilities that can be further improved with the availability of additional high-quality experimental results

Distinct Roles of Phosphoinositide-3 Kinase and Phospholipase Cγ2 in B-Cell Receptor-Mediated Signal Transduction

During B-cell receptor (BCR) signaling, phosphoinositide-3 kinase (PI3K) is thought to function upstream of phospholipase Cγ2 (PLCγ2). PLCγ2 deficiency specifically impedes transitional type 2 (T2) to follicular (FO) mature B-cell transition. Here, we demonstrate that PI3K deficiency specifically impaired T2-to-FO mature B-cell transition and marginal zone B-cell development. Furthermore, we investigated the functional relationship between PI3K and PLCγ2 using PI3K(−/−), PLCγ2(−/−), and PI3K(−/−) PLCγ2(−/−) B cells. Interestingly, PLCγ2 deficiency had no effect on BCR-mediated PI3K activation, whereas PI3K deficiency only partially blocked activation of PLCγ2. Moreover, whereas PI3K(−/−) PLCγ2(−/−) double deficiency did not affect hematopoiesis, it resulted in embryonic lethality. PI3K(−/−) PLCγ2(−/−) fetal liver cells transplanted into B-cell null JAK3(−/−) mice failed to restore development of peripheral B cells and failed to progress through early B-cell development at the pro-B- to pre-B-cell transition, a more severe phenotype than was observed with either PI3K or PLCγ2 single-deficiency B cells. Consistent with this finding, BCR signaling was more severely impaired in the absence of both PI3K and PLCγ2 genes than in the absence of either one alone. Taken together, these results demonstrate that whereas PI3K functions upstream of PLCγ2, activation of PLCγ2 can occur independently of PI3K and that PI3K and PLCγ2 also have distinct functions in BCR signal transduction

Phospholipase Cγ2 Contributes to Light-Chain Gene Activation and Receptor Editing▿

Phospholipase Cγ2 (PLCγ2) is critical for pre-B-cell receptor (pre-BCR) and BCR signaling. Current studies discovered that PLCγ2-deficient mice had reduced immunoglobulin λ (Igλ) light-chain usage throughout B-cell maturation stages, including transitional type 1 (T1), transitional type 2 (T2), and mature follicular B cells. The reduction of Igλ rearrangement by PLCγ2 deficiency was not due to specifically increased apoptosis or decreased proliferation of mutant Igλ+ B cells, as lack of PLCγ2 exerted a similar effect on apoptosis and proliferation of both Igλ+ and Igκ+ B cells. Moreover, PLCγ2-deficient IgHEL transgenic B cells exhibited an impairment of antigen-induced receptor editing among both the endogenous λ and κ loci in vitro and in vivo. Importantly, PLCγ2 deficiency impaired BCR-induced expression of IRF-4 and IRF-8, the two transcription factors critical for λ and κ light-chain rearrangements. Taken together, these data demonstrate that the PLCγ2 signaling pathway plays a role in activation of light-chain loci and contributes to receptor editing

Discovery of dibenzyl amide derivatives as novel CXCR4 modulators against inflammatory bowel disease

The CXCR4/CXCL12 chemokine axis demonstrates significant potential in the treatment of inflammatory bowel disease (IBD) due to its crucial roles in inflammatory and immune responses. Modulating the CXCR4/CXCL12 pathway can be an effective therapeutic approach to ameliorate the inflammatory state of IBD. In this study, a novel series of meta-dibenzyl amide derivatives were designed and synthesized based on the lead compound AMD3100 and its structurally modified derivatives. Both in vitro and in vivo assays conclusively established that these compounds exhibited potent CXCR4 antagonism and anti-inflammatory activity. Compound 5t demonstrated superior inhibitory rates of binding affinity and chemotaxis of CXCR4+ cells compared to AMD3100. Furthermore, compound 5t notably reduced swelling volume and tissue thickness in the carrageenan-induced mouse paw edema model. Most importantly, in the dextran sodium sulfate (DSS)-induced colitis model, compound 5t significantly mitigated colonic inflammation on both macroscopic and microscopic levels, while suppressing the expression of inflammatory factors and myeloperoxidase (MPO). These findings unequivocally establish the immense potential of compound 5t in the treatment of IBD