Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood–brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood–brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.

Follicular helper T (TFH) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naïve T cells are differentiating into TFH cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). TFH cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and TFH cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in TFH cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and TFH cell differentiation. TFH cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of TFH cells. The miR-17-92 cluster induces Bcl-6 and TFH cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (TFR) cells are studied as thymus-derived CXCR5+PD-1+Foxp3+ Treg cells that play a significant role in limiting the GC response. Regulation of TFH cell differentiation and the GC reaction via miRNA and TFR cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect TFH cell differentiation, and the role of TFH cells in autoimmune diseases.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPARγ ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4-PPARγKO mice to investigate PPARγ-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of IκBα, Sirt1, and Foxo1, which are inhibitors of NF-κB, was observed in PPARγ-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4-PPARγKO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (TFH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPARγKO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.

We report a multi-epoch, simultaneous 22 GHz H 2 O and 44 GHz Class I CH 3 OH maser line survey toward 180 intermediate-mass young stellar objects, including 14 Class 0, 19 Class I objects, and 147 Herbig Ae/Be stars. We detected H 2 O and CH 3 OH maser emission toward 16 (9 %) and 10 (6 %) sources with 1 new H 2 O and 6 new CH 3 OH maser sources. The detection rates of both masers rapidly decrease as the central (proto)stars evolve, which is contrary to the trends in high-mass star-forming regions. This suggests that the excitations of the two masers are closely related to the evolutionary stage of the central (proto)stars and the circumstellar environments. H 2 O maser velocities deviate on average 9 km s −1 from the ambient gas velocities whereas CH 3 OH maser velocities match quite well with the ambient gas velocities. For both maser emissions, large velocity differences (|v H 2 O − v sys | > 10 km s −1 and |v CH 3 OH − v sys | > 1 km s −1 ) are mostly confined to Class 0 objects. The formation and disappearance of H 2 O masers is frequent and their integrated intensities change by up to two orders of magnitude. In contrast, CH 3 OH maser lines usually show no significant change in intensity, shape, or velocity. This is consistent with the previous suggestion that H 2 O maser emission originates from the base of an outflow while 44 GHz Class I CH 3 OH maser emission arises from the interaction region of the outflow with the ambient gas. The isotropic maser luminosities are well correlated with the bolometric luminosities of the central objects. The fitted relations are L H 2 O = 1.71 × 10 −9 (L bol ) 0.97 and L CH 3 OH = 1.71 × 10 −10 (L bol ) 1.22 .

This study showed that arthroscopic partial repair may produce initial improvement in selected outcomes at 2-year follow-up. However, about half of the patients in the study were not satisfied with their outcomes, which had deteriorated over time. Preoperative fatty infiltration of the teres minor was the only factor that correlated with worse final outcomes and poor satisfaction after arthroscopic partial repair.

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Background: RAP80, a component of the BRCA1-A complex, is crucial in the cell cycle checkpoint and DNA damage repair. Results: RAP80 phosphorylation by Cdk1 is important for sensitivity to ionizing radiation and G 2 /M checkpoint control. Conclusion: Cdk1-mediated RAP80 phosphorylation is important for the DNA damage response. Significance: The findings provide new implications for the interplay of the DNA damage signaling pathway and RAP80 phosphorylation.