Regulation of neuroinflammatory properties of glial cells by T cell effector molecules

Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.

All-transRetinoic Acid Regulates Th1/Th2 Balance in CD4+T cells When GATA-3 is Deficient

The essential effect of vitamin A on immune function occurs through various mechanisms including direct effect on ThloTh2 balance modulation. However, it is unclear whether or not vitamin A can regulate Thl-Th2 balance under a strong Thl-polarizing condition. Therefore, the purpose of our study was to examine the effect of vitamin A metabolite allotrans retinoic acid （ATRA） on ThloTh2 differentiation in CD4~ T cells under GATA-3 deficiency, which can induce Thl-polarizing condition. In the present study, GATA-3 deficiency T cells were induced by siRNA and checked by real-time quantitative PCR and western blot. GATA-3 deficiency CD4＋ T cells and normal CD4＋ T were treated for 48 h with or without ATRA.

Role of RANTES and Its Receptor in Gastric Cancer Metastasis

This study examined the role of regulated upon activation normal T cell expressed and secreted（RANTES） and its receptor C-C chemokine receptor type 5（CCR5） in gastric cancer metastasis and the associated mechanism.The expression of RANTES and CCR5 was detected by using immunohistochemical staining and Western blotting in the gastric cancer tissues obtained from 60 gastric cancer patients with or without lymph node metastasis（n=30 in each）.The results showed that the expression levels of RANTES and CCR5 were higher in gastric cancer with lymph node metastasis than in that without metastasis（P0.05）.The expression levels of RANTES in 30 lymph nodes with cancerous invasion were higher than in 30 normal lymph nodes（P0.05）.Chemotactic test revealed that the number of migrating gastric cancer cells（n=295.0±54.6） induced by the protein of cancer-invading lymph nodes was greater than that by the protein mixture from cancer-invading lymph nodes and RANTES antibody（n=42.5±11.6）（P0.05）.RT-PCR showed that the expression levels of the main Th1 cytokines（IL-2,γ-IFN） were lower in gastric cancer with lymph node metastasis（2.22±0.90,3.26±1.15 respectively） than in that without metastasis（3.07±1.67,4.77±1.52 respectively）（P0.05）,but the expression level of the main Th 2 cytokine（IL-10） was higher in gastric cancer with lymph nodes metastasis（6.06±2.04） than in that without metastasis（4.88±1.87）（P0.05）.It was concluded that RANTES and its receptor CCR5 may contribute to gastric cancer metastasis through influencing the balance of Th1/Th2.RANTES and CCR5 may become a marker of gastric cancer metastasis.

Ubiquitin-specific peptidase 18 regulates the differentiation and function of Treg cells

Ubiquitin-specific peptidase 18(USP18)plays an important role in the development of CD11b^(+)dendritic cells(DCs)and Th17 cells,however,its role in the differentiation of other T cell subsets,especially in regulatory T(Treg)cells,is unknown.In our study,we used Usp18 K0 mice to study the loss of USP18 on the impact of Treg cell differentiation and function.We found that USP18 deficiency upregulates the differentiation of Treg cells,which may lead to disrupted homeostasis of peripheral T cells,and downregulates INF-y,IL-2,IL-17A producing CD4^(+)T cells and INF-γproducing CD8^(+)T cells.Mechanistically,we also found that the upre-gulation of Tregs is due to elevated expression of CD25 in Usp18 KO mice.Finally,we found that the suppressive function of Usp18 KO Tregs is downregulated.Altogether,our study was the first to identify the role of USP18 in Tregs differentiation and its suppressive function,which may provide a new reference for the treatment of Treg function in many autoimmune diseases,and USP18 can be used as a new therapeutic target for precise medical treatment.

Construction of chlorogenic acid-containing liposomes with prolonged antitumor immunity based on T cell regulation

As a potential cancer immunotherapeutic agent,chlorogenic acid(CHA)has entered phase II clinical trials in China as a lyophilized powder formulation for treating glioma.However,the in vivo instability of CHA necessitates daily intramuscular injections,resulting in patient noncompliance.In this study,CHA-phospholipid complex(PC)-containing PEGylated liposomes(CHA-PC PEG-Lipo,named as CPPL),with CHA-PC as the drug intermediate,were prepared to lower the administration frequency.CPPL demonstrated excellent physicochemical properties,enhanced tumor accumulation,and inhibited tumor growth even when the administration interval was prolonged to 4 days when compared to a CHA solution and CHA-PC loaded liposomes(CHA-PC Lipo,labeled as CPL),both of which only demonstrated antitumor efficacy with once-daily administration.Further evaluation of the in vivo antitumor immune mechanism suggested that the extended antitumor immune efficacy of CPPL could be attributed to its distinct immune-stimulating mechanism when compared with CHA solution and CPL,such as stimulating both CD4+and CD8+T cell infiltration,inhibiting myeloid-derived suppressor cell expression,reducing the expression of Th2 related factors,and notably,increasing the memory T cells in tumor tissues.This CHA-containing formulation could reduce the frequency of in vivo CHA administration during cancer treatment via T cells,especially memory T cell regulation.

The Qa-1 Dependent CD8^+ T Cell Mediated Regulatory Pathway

The immune system has evolved a variety of regulatory mechanisms to ensure the peripheral self-tolerance as well as the optimal capacity to elicit effective anti-infection immunity. At present, there is no satisfactory conceptual framework to explain how the peripheral immunity is regulated at a biological system level, which enables the immune system to perform its essential functions to mount effective immunity to virtually any foreign antigens but avoid harmful immune responses to self. In this regard, during the past few years, an “affinity/avidity model of peripheral T cell regulation” has been proposed and tested, which opens up a new paradigm to understand how the peripheral immunity, to both self and foreign antigens, is regulated. The paradigm is based on the discovery of a subset CD8^＋ T cells with TCRs which specifically recognize a unique set of self-peptides presented by the MHC class Ib molecule Qa-I differentially expressed on T cells as a function of the affinity/avidity of T cell activation. These Qa-1 restricted CD8^＋ T cells represent an example of how the immune system utilizes a unified mechanism to regulate adaptive immunity to both self and foreign antigens. Thus, by selectively down-regulating T cells of intermediate affinity/avidity, to any antigens, the immune system controls the adaptive immunity without the necessity to distinguish self from non-self in the periphery at the level of T cell regulation. Cellular ＆ Molecular Immunology. 2005;2（3）：161-167.

Effect of Xinfeng Capsule(新风胶囊) on the Cardiac Function in Patients with Rheumatoid Arthritis

Objective： To study the changes in cardiac function of rheumatoid arthritis （RA） patients and to observe the effect of Xinfeng Capsule （新风胶囊 XFC） on them. Methods： Sixty-eight RA patients were randomly assigned to two groups by a lottery： 38 patients in the treatment group treated orally with XFC, 3 capsules, thrice a day, and 30 in the control group treated with Fengshi Gutong Capsule （风湿骨痛胶囊, FSGTC）, 4 capsules, twice a day, 30 days as one course of treatment, and two courses were given for both groups. A normal control （NC） group including 20 healthy subjects was set up. The clinical efficacy was compared between the two treated groups. The changes in cardiac function, including early diastolic peak flow velocity （E）, late diastolic peak flow velocity （A）, left ventricular fraction shortening （FS）, and E/ A, as well as uric acid （UA）, erythrocyte sedimentation rate （ESR）, α-acid glycoprotein （α-AGP）, and hypersensitive C-reaction protein （hs-CRP）, were observed. The regulation T cell was determined with flow cytometry. Results： （1） The total effective rate in the treatment group and the control group was 92.1% （35/38） and 70.0% （21/30）, respectively. Significant difference was shown between them （P〈0.05）. （2） Compared with those of the NC group, E peak, E/A ratio, and FS of RA patients were lower （P〈0.01）, while A peak was higher （P〈0.01）. Moreover, A peak of the treatment group after treatment was significantly lower （P〈0.05） and E/A ratio was significantly higher （P〈0.05） as compared with those of the control group. （3） The improvement in the treatment group in reducing UA and hs-CRP was superior to those of the control group （P〈0.05）. In addition, the improvement in α-AGP, CD4＋CD25＋ Treg, and CD4＋CD25＋CD12T Treg of the treatment group was obvious as compared with the control group, although the difference was not statistically significant. （Conclusions： The descendent of cardiac function exists in RA patients. XFC could improve cardiac function of RA patients, which is superior to FSGTC. Its mechanism may be related to its effect on raising CD4＋CD25＋Treg and CD4＋CD25＋CD127- Treg cells, decreasing UA, α-AGP, and hs-CRP levels, reducing immune inflammation, adjusting the overall balance of immune response, and thus improving the cardiac function of RA patients.

Dendrobium nobile protects against ovalbumin-induced allergic rhinitis by regulating intestinal flora and suppressing lung inflammation

Antibiotic exposure-induced dysbiosis of the intestinal flora increases the risk of developing allergic rhinitis.Hence,regulating the balance of intestinal flora may be useful for preventing and treating allergic rhinitis.However,the underlying mechanism is unclear.Dendrobium nobile(Shihu)exhibits anti-inflammatory and immune activities.Hence,in this study,we investigated the mechanism via which Shihu may improve allergic rhinitis.Mouse models of allergic rhinitis with intestinal flora dysbiosis(Model-D,antibiotics induce intestinal flora dysbiosis with ovalbumin-induced allergy)and normal intestinal flora with allergic rhinitis(Model-N,ovalbumin-induced allergy)were established.The effect of Shihu on intestinal flora and inflammation caused during allergic rhinitis were analyzed.Allergic symptoms,infiltration of hematoxylin and eosin in the lungs and nose,and the release of various factors[interleukin(IL)-2,IL-4,IFN-y,IL-6,IL-10,and IL-17]in the lungs were evaluated.The results indicate that intestinal flora dysbiosis exacerbated lung and nose inflammation in allergic rhinitis.However,treatment with the Shihu extract effectively reversed these symp-toms.Besides,the Shihu extract inhibited the PI3K/AXT/mTOR pathway and increased the level of Forkhead box protein in the lungs.Additionally,the Shihu extract reversed intestinal flora dysbiosis at the phylum and genus levels and improved regulator T cell differentiation.Furthermore,in the Model-D group,the Shihu extract inhibited the decrease in the diversity and abundance of the intestinal flora.Screening was performed to determine which intestinal flora was positively correlated with Treg differentiation using Spearman5 s correlation analysis.In conclusion,we showed that Shihu extract restored the balance in intestinal flora and ameliorated inflammation in the lungs of allergic rhinitis mice and predicted a therapeutic new approach using Traditional Chinese Medicine to improve allergic rhinitis.