CD4+CD25+Foxp3+ Regulatory T Cells Contribute in Liver Fibrosis Improvement with Interferon Alpha

The aim of this study is to investigate the optimal dose, treatment time, and possible immunologic mechanisms of interferon alpha (IFN-α) in the treatment of liver fibrosis. Mice were injected intraperitoneally with 10 % carbon tetrachloride to induce liver fibrosis, except in the normal control group. The experimental mice were randomly divided into four groups: physiological saline group, 20 U/gb wt IFN-α group, 40 U/gb wt IFN-α group, and 60 U/gb wt IFN-α group. After 3 and 6 weeks, type I collagen was detected in liver by hematoxylin and eosin (HE) stain, Masson’s trichrome stain, and immunohistochemical staining. The number of CD8⁺ T cells, the number of CD4⁺CD25⁺Foxp3⁺ Tregs and the activation of CD4⁺ T cells were detected in liver and spleen. Beneficial effects were observed in the 40 U/gb wt IFN-α group by pathological analysis. The number of CD8⁺ T cells in the liver was significantly lower in mice receiving middle-dose IFN-α therapy as compared to mice receiving physiological saline (P?<?0.05), while CD4⁺CD25⁺Foxp3⁺ Tregs and activation of CD4⁺ T cells in the liver were significantly higher in the therapeutic group than in the physiological saline group (P?<?0.05). CD8⁺ T cells (r?=?0.3796) and activated CD4⁺ T cells (r?=?0.2437) were found to be positively correlated with the degree of liver fibrosis. CD4⁺CD25⁺Foxp3⁺ Tregs (r?=??0.7932) was found to be negatively correlated with the degree of liver fibrosis. IFN-α can inhibit liver fibrosis following 6 weeks of middle-dose IFN-α therapy by upregulating CD4⁺CD25⁺Foxp3⁺ Tregs and suppressing CD8⁺ T cells.     

Distinct Contributions of CD4+ and CD8+ T Cells to Pathogenesis of Trypanosoma brucei Infection in the Context of Gamma Interferon and Interleukin-10

Although gamma interferon (IFN-γ) and interleukin-10 (IL-10) have been shown to be critically involved in the pathogenesis of African trypanosomiasis, the contributions to this disease of CD4⁺ and CD8⁺ T cells, the major potential producers of the two cytokines, are incompletely understood. Here we show that, in contrast to previous findings, IFN-γ was produced by CD4⁺, but not CD8⁺, T cells in mice infected with Trypanosoma brucei. Without any impairment in the secretion of IFN-γ, infected CD8^−/− mice survived significantly longer than infected wild-type mice, suggesting that CD8⁺ T cells mediated mortality in an IFN-γ-independent manner. The increased survival of infected CD8^−/− mice was significantly reduced in the absence of IL-10 signaling. Interestingly, IL-10 was also secreted mainly by CD4⁺ T cells. Strikingly, depletion of CD4⁺ T cells abrogated the prolonged survival of infected CD8^−/− mice, demonstrating that CD4⁺ T cells mediated protection. Infected wild-type mice and CD8^−/− mice depleted of CD4⁺ T cells had equal survival times, suggesting that the protection mediated by CD4⁺ T cells was counteracted by the detrimental effects of CD8⁺ T cells in infected wild-type mice. Interestingly, CD4⁺ T cells also mediated the mortality of infected mice in the absence of IL-10 signaling, probably via excessive secretion of IFN-γ. Finally, CD4⁺, but not CD8⁺, T cells were critically involved in the synthesis of IgG antibodies during T. brucei infections. Collectively, these results highlight distinct roles of CD4⁺ and CD8⁺ T cells in the context of IFN-γ and IL-10 during T. brucei infections.     

Underexpression of TIM-3 and Blunted Galectin-9-Induced Apoptosis of CD4+ T Cells in Rheumatoid Arthritis

The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls (p = 0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls (p = 0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p = 0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target.     

Suppression of CD4+ Effector Responses by Naturally Occurring CD4+ CD25+ Foxp3+ Regulatory T Cells Contributes to Experimental Cerebral Malaria

The role of naturally occurring CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4⁺ T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4⁺ T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4⁺ T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4^−/−) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.     

CD4+CD25+Foxp3+T细胞在子痫前期中作用机制的研究

目的 探讨子痫前期(PE)患者外周血中CD4+CD25+Foxp3+T细胞及胎盘组织Foxp3的表达水平.方法 73例PE患者分为MPE组(轻度PE,38例)和SPE组(重度PE,35例),以正常的孕妇作为对照组;采用流式细胞术(FCM)检测外周血中CD4+CD25+Foxp3+T细胞的表达水平,采用免疫组化法(IHC)检测胎盘组织Foxp3的表达水平;将Foxp3与CD4+CD25+Foxp3+T、胎盘重量和阿氏(Apgar)评分进行Spearman相关性分析.结果 SPE组、MPE组外周血中CD4+CD25+Foxp3+T细胞表达水平分别为4.23±0.74％、6.58±0.8％,均低于对照组的7.01±0.95 ％(P＜0.05),SPE组外周血中CD4+CD25+Foxp3+T细胞表达水平低于MPE组(P ＜0.05);SPE组、MPE组胎盘组织中Foxp3的阳性表达率分别为28.57％、47.37％,均低于对照组的82.76％(P ＜0.05),SPE组胎盘组织中Foxp3的阳性表达率显著低于MPE组(P＜0.05);胎盘组织中Foxp3的阳性表达率与CD4+CD25+Foxp3+T细胞表达水平、胎盘重量及Apgar评分均呈正相关(P＜0.01).结论 PE与外周血中CD4+CD25+Foxp3+T细胞表达水平下降密切相关.     

CD38+CD8+ and CD38+CD4+ T Cells and IFN Gamma (+874) Polymorphism Are Associated with a Poor Virological Outcome

The main objective of the work was to evaluate the use of CD38 on T lymphocytes, IFNγ (+874 A/T), and IL-10 (?1082 A/G) polymorphisms in HIV-infected patients under antiretroviral (ARV) therapy. Sixty-one patients were selected at the outpatient clinic for HIV infection at the Hospital São José de Doenças Infecciosas, Fortaleza, Ceará, Brazil. The patients were classified into two groups, according to viral load after one year of ARV therapy. In the aviremic group (group I), a reduction of 35.5% of CD38+CD4+ T cells was observed (p = 0.02) and 49.3% of CD38+CD8+ T cells (p = 0.001). In the viremic group (group II), a reduction of 37.2% of CD38+CD4+ T cells (p = 0.067), and 21.4% of CD38+CD8+ T cells (p = 0.60) occurred. No association was found between IL-10 (?1082) polymorphism and the type of response to ARV therapy. Regarding the gene polymorphism on IFNγ (+874 T/A), 73.34% of group I and 33.3% of group II presented the AA genotype. The relative risk of the individuals carrying AA genotype or the A allele and not being able to suppress the viral load level after one year of ARV therapy was 3.44 (1.25–9.45; p = 0.014) or 2.35 (1.05–5.26; p = 0.027), respectively. Our data suggested that an augmented frequency of activated CD38+CD8+ T cells as well as the presence of the A allele of IFNγ polymorphism could contribute to a reduced virological suppression in patients under antiretroviral therapy.     

Increased Frequency of CD4+CD25highFoxP3+ Regulatory T Cells in Patients with Hepatocellular Carcinoma

Accumulating evidence suggests regulatory T cells (Tregs) are associated with impaired antitumor responses. However, the relationship between the CD4(+)CD25(high)FoxP3(+) Treg and hepatocellular carcinoma (HCC) has not been well investigated. Levels of CD4(+)CD25(high)FoxP3(+) Tregs in peripheral blood mononuclear cells (PBMCs) from HCC patients and healthy donors, tumor infiltrating lymphocytes (TILs) extracted from HCC, and hepatic lymphocytes extracted from resected liver were measured by flow cytometry, and their effects on T-cell proliferation was determined by (3)H-thymidine incorporation. Serum levels of interleukin (IL)-10 and transforming growth factor (TGF)-β1 were measured by enzyme linked immunosorbent assay. The frequency of Tregs in PBMCs from HCC patients was higher than that from healthy donors. Similarly, the frequency of Tregs in TILs was higher than that of hepatic lymphocytes. On the other hand, the (3)H-thymidine uptake by TILs and PBMCs from HCC patients was decreased drastically when compared to the counterparts from normal controls. Furthermore, serum IL-10 and TGF-β1 levels increased significantly in HCC patients when compared to the healthy donors. This study identified an increased frequency of CD4(+)CD25(high)FoxP3(+) Tregs in patients with HCC. The elevated serum IL-10, TGF-β1 levels also correlated with impaired antitumor responses in these patients. Further effort is needed to establish new immunotherapeutic strategies designed to modulate Tregs to promote a competent antitumor response.     

Upregulation of TIM-3 and PD-1 on CD4+ and CD8+ T Cells Associated with Dysfunction of Cell-Mediated Immunity after Colorectal Cancer Operation

Surgery has been reported to suppress cell-mediated immunity; however, the detailed mechanisms responsible for this remain unclear. We obtained information on expressions of T-cell immunoglobulin domain and mucin domain 3 (TIM-3) and programmed cell death 1 (PD-1) on both CD4+ and CD8+ T cells postoperatively from colorectal cancer patients and evaluated by multicolor flow cytometry. The functions of CD4+ and CD8+ T cells based on TIM-3 and PD-1 expressions were determined by quantitating the concentration of interferon-γ (IFN-γ) by enzyme-linked immunosorbent assay. The study demonstrated a rapid and significant decrease in number of total lymphocytes, CD4+ T cells and CD8+ T cells. These immune cells reached the minimum on day 1 and then increased, but still significantly decreased on days 3 and 7. The frequency of PD-1+CD4+ T cells and TIM-3+CD4+ T cells significantly increased after colorectal surgery. IFN-γ secretion by PD-1+TIM-3+CD4+ T cells was significantly decreased compared to secretion by either PD-1+TIM3-CD4+ T cells or PD-1–TIM-3–CD4+ T cells. Furthermore, IFN-γ secretion by PD-1+TIM-3+CD8+ T cells was significantly decreased compared to secretion by either PD-1–TIM-3+CD8+ T cells or PD-1–TIM-3–CD8+ T cells. The expression of PD-1 and TIM-3 was closely related to impaired cell-mediated immunity that was observed after surgery for colorectal cancer. New treatment targeting TIM-3 and PD-1 on CD4+ and CD8+ T cells during the perioperative period may provide a breakthrough in the treatment of colorectal cancer patients.     

Impaired Gamma Interferon Production by Cells from Patients with Lymphoproliferative Disorders of Mature T and NK Cells

We investigated interferon (IFN) production by peripheral blood mononuclear cells from four patients with chronic OKT4 T-lymphocytic leukaemia and three patients with abnormal expansions of granular lymphocytes. No spontaneous production of IFN-gamma was found in supernatants of cultures from both patients and normal controls. However, whereas the enzyme galactose oxidase or staphylococcal enterotoxin B was able to induce IFN-gamma production by normal cells, no production could be obtained in the cells under study. The possibility that this lack of production might have been attributed to an excess of N-acetylneuraminic acid masking galactose residues or to a defect of monocyte accessory cells was ruled out either by pre-treating the cells with neuraminidase or by adding normal adherent cells to the cultures, both of which resulted in a lack of production. On the contrary, the calcium ionophore A23187 (considered to act as a second specific step, following oxidation of galactose residues, toward genetic derepression of IFN-gamma) induced considerable IFN-gamma production in all the three tested patients. It can be concluded that, although in rare cases, as previously reported by other authors, cells from patients with T or NK lymphoproliferative disorders may spontaneously produce IFN-gamma, this is not a general mechanism that underlies the disease. In fact, in all our cases a defect of IFN-gamma production was found. This defect seems due to an alteration at the membrane level of the galactose-containing glycoproteins and can be restored by induction with a calcium ionophore.     

Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes

Among the several mechanisms known to be involved in the establishment and maintenance of immunological tolerance, the activity of CD4+CD25+ regulatory T lymphocytes has recently incited most interest because of its critical role in inhibition of autoimmunity and anti-tumor immunity. Surprisingly, very little is known about potential genetic modulation of intrathymic regulatory T lymphocyte development. We show that distinct proportions of CD4+CD25+FoxP3+ regulatory T cells are found in thymi of common laboratory mouse strains. We demonstrate that distinct levels of phenotypically identical regulatory T cells develop with similar kinetics in the mice studied. Our experimental data on congenic mouse strains indicate that differences are not caused by the distinct MHC haplotypes of the inbred mouse strains. Moreover, the responsible loci act in a thymocyte-intrinsic manner, confirming the latter conclusion. We have not found any correlation between thymic and peripheral levels of regulatory T cells, consistent with known homeostatic expansion and/or retraction of the peripheral regulatory T cell pool. Our data indicate that polymorphic genes modulate differentiation of regulatory T cells. Identification of responsible genes may reveal novel clinical targets and still elusive regulatory T cell-specific markers. Importantly, these genes may also modulate susceptibility to autoimmune disease.     

Decreased Levels of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Patients with Primary Antiphospholipid Syndrome

Introduction

CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cell dysfunction has been documented in various autoimmune disorders, but not in antiphospholipid syndrome (APS) so far.

Methods

In this cross-sectional study, we aim to investigate CD4⁺CD25⁺Foxp3⁺ Treg cells, CD3⁺CD19^? T cells and CD3^?CD19⁺ B cells in patients with primary APS and healthy controls. Cell subtypes were immunophenotyped using specific monoclonal antibodies (anti-CD3 CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3, anti-CD19 PE) and flow cytometry.

Results

Twenty patients with APS and 20 age- and sex-matched controls were studied. The percentage of total lymphocytes, activated Th cells (CD4+CD25+), Treg cells and CD3^?CD19⁺ B cells were found significantly lower in APS patients as compared to controls (all p?<?0.05).

Conclusion

A dysfunction in CD4⁺CD25⁺Foxp3⁺ Treg cells may represent one of the mechanisms leading to autoimmunity in APS patients. The decreased number of CD3^?CD19⁺ B cells of APS patients warrants further elucidation.     

Circulating CD3+ CD4+ CD+ T lymphocytes in multiple sclerosis

Triple-antibody flow cytometry was used to search for distinctive populations of peripheral blood lymphocyte immunophenotypes in multiple sclerosis (MS). Using monoclonal antibodies to the cell surface markers CD3, CD4, and CD8, T cell subsets were quantified on a cohort of 31 MS patients (not treated with corticosteroids for at least 6 months), 30 healthy donors, and 14 patients with other autoimmune diseases (also corticosteroid treatment-free for at least 6 months). Untreated MS patients displayed a significantly greater population of CD3+CD4+CD8+ circulating T cells than healthy donors (P = 0.023). Patients with other autoimmune diseases displayed mean populations of CD3+CD4+CD8+ cells greater than normal donors and less than MS, but not significantly different from either. An additional 45 MS patients who had received corticosteroid therapy within the previous 6 months were phenotyped. Treatment of symptomatic MS with corticosteroids was associated with a smaller population of circulating CD3+CD4+CD8+ cells. Some MS patients have significantly greater numbers of peripheral blood T lymphocytes simultaneously expressing CD3, CD4, and CD8 surface markers than healthy donors and this population of cells may be reduced by corticosteroids treatment. This triple positive phenotype may be a manifestation of a systemic immune abnormality in MS.     

Roles of CD4+ T Cells and Gamma Interferon in Protective Immunity against Babesia microti Infection in Mice

Babesia microti produces a self-limiting infection in mice, and recovered mice are resistant to reinfection. In the present study, the role of T cells in protective immunity against challenge infection was examined. BALB/c mice which recovered from primary infection showed strong protective immunity against challenge infection. In contrast, nude mice which failed to control the primary infection and were cured with an antibabesial drug did not show protection against challenge infection. Treatment of immune mice with anti-CD4 monoclonal antibody (MAb) diminished the protective immunity against challenge infection, but treatment with anti-CD8 MAb had no effect on the protection. Transfer of CD4(+) T-cell-depleted spleen cells resulted in higher parasitemia than transfer of CD8(+) T-cell-depleted spleen cells. A high level of gamma interferon (IFN-gamma), which was produced by CD4(+) T cells, was observed for the culture supernatant of spleen cells from immune mice, and treatment of immune mice with anti-IFN-gamma MAb partially reduced the protection. Moreover, no protection against challenge infection was found in IFN-gamma-deficient mice. On the other hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or tumor necrosis factor alpha did not affect protective immunity. These results suggest essential requirements for CD4(+) T cells and IFN-gamma in protective immunity against challenge infection with B. microti.     

Cytotoxicity and Secretion of Gamma Interferon Are Carried Out by Distinct CD8 T Cells during Mycobacterium tuberculosis Infection

The host immune response is generally sufficient to contain Mycobacterium tuberculosis infection. It does not, however, efficiently prevent subsequent infection with M. tuberculosis or provide sterilizing immunity. While the understanding of the immune response generated against this pathogen is incomplete, improvements have been achieved due to advances in immunological tools. In this study, we analyzed the multifunctional nature of primary and memory CD8 T-cell responses generated during murine M. tuberculosis infection. We generated a recombinant M. tuberculosis strain expressing ovalbumin (OVA) epitopes in order to expand the peptides for the detection of CD8 T cells during M. tuberculosis infection and enable us to use OVA-specific reagents. Our results indicate that the majority of M. tuberculosis-specific CD8 T cells are limited to either cytotoxicity or the secretion of gamma interferon (IFN-γ), with cytotoxicity being far more prevalent than IFN-γ secretion. Memory CD8 T cells responded earlier and reached higher levels in the lungs than naïve CD8 T cells, as was expected. They were, however, less cytotoxic and secreted less IFN-γ than newly primed CD8 T cells, suggesting that one factor contributing to bacterial persistence and lack of sterilizing immunity may be the low quality of memory cells that are generated.Mycobacterium tuberculosis, the pathogen causing tuberculosis, is an escalating global health threat that is spread between people by aerosolized droplets. While a subset of people develop primary disease and are infectious, most people contain the infection through a successful immune response. Typing of M. tuberculosis strains has shown that people can be infected simultaneously or sequentially with different strains of M. tuberculosis (29, 37). Thus, immune responses that are sufficient to contain an initial infection may be unable to prevent the establishment of subsequent M. tuberculosis infections. In addition, persons treated for tuberculosis with antimycobacterial drugs can be reinfected and develop disease (36). This is also true in animal models (8, 16, 32). This suggests that memory responses generated during previous mycobacterial infections are not generally capable of protecting against new infections or disease.It is currently unknown which, if any, immune functions can protect against establishment of infection. In terms of T-cell responses, gamma interferon (IFN-γ) and tumor necrosis factor can activate infected macrophages to induce antimicrobial activity, while cytolysis of infected cells can kill the bacterium or release it to be taken up by healthy cells that are better able to contain it (12, 21). Most studies of the role of CD8 T cells during M. tuberculosis infection have focused on either IFN-γ secretion or cytotoxicity. A few studies have examined both functions but not on a single-cell basis (6, 17, 19). These studies indicated that CD8 T-cell-mediated IFN-γ secretion and cytotoxicity peak in the lungs at 4 weeks postinfection. IFN-γ secretion subsequently decreases, while the results differ as to whether cytotoxicity decreases. This difference may be due to variation between mouse strains and epitopes or the techniques used to assess cytotoxicity.In the current study, we demonstrate that most M. tuberculosis-specific CD8 T cells generated during primary infection were limited to either secretion of IFN-γ or cytotoxic function. There was a higher fraction of CD8 T cells with cytotoxic potential compared to those that produced IFN-γ. The CD8 T-cell memory response was similarly exclusive in function. Despite increased degranulation, cells responding during secondary infection were less cytotoxic than cells responding during primary infection. Induction of superior quality CD8 T cells may provide a benefit during M. tuberculosis infection, but a more detailed understanding of the complex T-cell response to M. tuberculosis is necessary for the development of future preventive and therapeutic strategies.     

Gamma interferon-producing CD4+ T lymphocytes in the lung correlate with resistance to infection with Mycobacterium tuberculosis

The human immune system efficiently limits the replication of Mycobacterium tuberculosis in most infected individuals. Only 5 to 10% of infected people develop clinical tuberculosis, a sign of the inability of the immune system to control the infection. We have studied the C3H/HeJ (C3H) and C57BL/6 (B6) inbred mouse strains, which differ in their susceptibility to tuberculosis, in order to ascertain the immunological determinants of a successful immune response against M. tuberculosis and to establish a system to identify genes that influence susceptibility to tuberculosis. We found that the resistant B6 mice were able to control infection in both the lung and spleen, while susceptible C3H mice were incapable of limiting bacteria growth, especially in the lung, and succumbed to infection within 4 weeks. We determined that the susceptibility of C3H mice was independent of the Toll-like receptor 4 (tlr4) genetic locus and allelic major histocompatibility complex differences. Although the splenic immune responses were similar in the two mouse strains, the local immune responses in the lungs of the infected mice differed greatly. The pulmonary immune response in resistant B6 mice was characterized by an early influx of both CD4+ and CD8+ lymphocytes that produced gamma interferon (IFN-gamma). In contrast, the immune response of C3H mice in the lung was characterized by a delayed and decreased influx of lymphocytes, which produced little IFN-gamma. These results suggest an important role for the early appearance of IFN-gamma-producing lymphocytes in the lung in resistance to infection with M. tuberculosis.     

Asthma Prevention by Lactobacillus Rhamnosus in a Mouse Model is Associated With CD4+CD25+Foxp3+ T Cells

Purpose

Probiotic bacteria can induce immune regulation or immune tolerance in allergic diseases. The underlying mechanisms have been recently investigated, but are still unclear. The aim of this study was to evaluate the protective effects of the probiotic Lactobacillus rhamnosus (Lcr35) in a mouse model of asthma and to identify its mechanism of action.

Methods

Lcr35 was administered daily by the oral route at a dosage of 1×10⁹ CFU/mouse in BALB/c mice for 7 days before the first sensitization. Clinical parameters and regulatory T (Treg) cells were examined. The role of CD4⁺CD25⁺Foxp3⁺ Treg cells was analyzed using a Treg cell-depleting anti-CD25 monoclonal antibody (mAb).

Results

Airway hyperresponsiveness, total IgE production, pulmonary eosinophilic inflammation, and splenic lymphocyte proliferation were suppressed after Lcr35 treatment. Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines in the serum were suppressed, and the percentage of CD4⁺CD25⁺Foxp3⁺ Treg cells in the spleen was significantly increased in the Lcr35 treatment group. Anti-CD25 mAb administration abolished the protective effects of Lcr35, indicating that CD4⁺ CD25⁺Foxp3⁺ Treg cells are essential in mediating the activity of Lcr35.

Conclusions

Oral administration of Lcr35 attenuated the features of allergic asthma in a mouse model and induced immune regulation by a CD4⁺CD25⁺Foxp3⁺ Treg cell-mediated mechanism.     

Regulators of Glucose Metabolism in CD4+ and CD8+ T Cells

Much like cancer cells, activated T cells undergo various metabolic changes that allow them to grow and proliferate rapidly. By adopting aerobic glycolysis upon activation, T cells effectively prioritize efficiency in biosynthesis over energy generation. There are distinct differences in the way CD4⁺ and CD8⁺ T cells process activation signals. CD8⁺ effector T cells are less dependent on Glut1 and oxygen levels compared to their CD4⁺ counterparts. Similarly the downstream signaling by TCR also differs in both effector T cell types. Recent studies have explored PI3K/Akt, mTORC, HIF1α, p70S6K and Bcl-6 signaling in depth providing definition of the crucial roles of these regulators in glucose metabolism. These new insights may allow improved therapeutic manipulation against inflammatory conditions that are associated with dysfunctional T-cell metabolism such as autoimmune disorders, metabolic syndrome, HIV, and cancers.     

CD4+ CD25+ T Cells Prevent Arthritis Associated with Borrelia Vaccination and Infection

CD4⁺ CD25⁺ T cells are a population of regulatory T cells associated with control of arthritis in anti-interleukin-17 antibody-treated Borrelia-vaccinated and challenged gamma interferon-deficient mice. Here, we present direct evidence that adoptive transfer of enriched CD4⁺ CD25⁺ T cells from these mice can prevent the development of arthritis in Borrelia-vaccinated and challenged mice. These findings establish a major role for CD4⁺ CD25⁺ T cells in the prevention of arthritis in Borrelia-vaccinated and challenged animals.