Comparative intracellular cytokine production by in vitro stimulated T lymphocytes from human umbilical cord blood (HUCB) and adult peripheral blood (APB).

To date over 400 HUCB transplants have been reported from different centers. It has been suggested that there is a reduced graft-versus-host-disease (GVHD) with HUCB compared to bone marrow transplantation. Since cytokine production by a cell is an indication of the cells function it is important to determinate the differences between APB and HUCB with respect to production of these soluble factors. Our aim was to analyse the intracellular cytokine production by HUCB and APB T lymphocytes with and emphasize on their possible role in GVHD. Heparinized HUCB samples from 8 normal full-term deliveries and 10 normal blood donors were stimulated 4 hours at 37 degrees C and 5% CO2 with phorbol 12-myristate 13-acetate (PMA) and lonomycin in the presence of brefeldine. Afterwards cells were stained with CD3, CD4 or CD8 in different combinations. Finally, after cell permeabilization, cells were stained with Il-2, Il-4 or IFN-gamma. Data acquisition was performed on a FACScan flow cytometer. Compared to APB, HUCB T lymphocytes produced less Il-2, Il-4 and IFN-gamma. In HUCB, Il-2, Il-4 and IFN-gamma were produced predominantly by CD4+ T cells. In APB, Il-2 and Il-4 were also produced predominantly by CD4+ cells compared with CD8+ T lymphocytes, however, IFN-gamma was produced by both CD4+ and CD8+ T cells. These results indicate that there are clear differences in the cytokine profile between T cells in APB and HUCB.     

Flow cytometric analysis of macaque whole blood for antigen-specific intracellular cytokine production by T lymphocytes

We report here the standardized conditions for stimulation of macaque whole blood samples with various protein or peptide antigens, and production of significant intracellular levels of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in CD4+ as well as CD8+ T lymphocytes. We observed significantly higher levels of TNF-alpha compared with IFN-gamma in both CD4+ and CD8+ T lymphocytes from all the macaque whole blood samples stimulated with staphylococcal enterotoxin B (SEB) as an antigen. Similarly, when whole blood samples from rhesus macaques immunized with an HIV envelope peptide cocktail vaccine were stimulated with either the peptide cocktail or recombinant gp160, we observed production of significant levels of TNF-alpha by both CD4+ and CD8+ T lymphocytes. These results strongly support the utility of the whole blood cytokine flow cytometry methodology for determining antigen-specific immune responses of macaques in vaccine studies.     

Effect of vitamin supplementation on cytokine response and on muscle damage after strenuous exercise

The present double-blinded, placebo-controlled study investigated whether antioxidant vitamin supplementation was able to modulate the cytokine and lymphocyte responses after strenuous eccentric exercise. Furthermore, muscle enzyme release was examined to see whether antioxidant treatment could reduce muscle damage. Twenty male recreational runners randomly received either antioxidants (500 mg of vitamin C and 400 mg of vitamin E) or placebo for 14 days before and 7 days after a 5% downhill 90-min treadmill run at 75% .VO(2 max). Although the supplemented group differed significantly with regard to plasma vitamin concentration before and after exercise when compared with the placebo group, the two groups showed identical exercise-induced changes in cytokine, muscle enzyme, and lymphocyte subpopulations. The plasma level of interleukin (IL)-6 and IL-1 receptor antagonist increased 20- and 3-fold after exercise. The plasma level of creatine kinase was increased sixfold the day after exercise. The concentrations of CD4+ memory T cells, CD8+ memory and na?ve T cells, and natural killer cells increased at the end of exercise. The total lymphocyte concentration was below prevalues in the postexercise period. In conclusion, the present study does not support the idea that exercise-induced inflammatory responses are induced by free oxygen radicals.     

Exercise-induced change in type 1 cytokine-producing CD8+ T cells is related to a decrease in memory T cells.

In response to exercise, both CD4(+) and CD8(+) T cells are mobilized to the blood, but the levels of these cells decline below preexercise values in the postexercise period. T cells are functionally polarized, depending on the cytokines they produce. Type 1 cells produce, e.g., interferon (INF)-gamma, whereas type 2 produce, e.g., interleukin (IL)-4. It was recently demonstrated that exercise induces a decrease in the percentage of type 1 T cells. The present study further investigated the mechanisms underlying the exercise-induced shift in the balance between type 1 and type 2 cytokine-producing cells. Seven healthy men performed 1.5 h of treadmill running with blood samples drawn before exercise, at the end of exercise, and 2 h after exercise. Intracellular expression of IFN-gamma, IL-2, and IL-4 was detected in CD4(+) and CD8(+) T cells after stimulation with phorbol 12-myristate 13-acetate and ionomycin. Intracellular expression of IFN-gamma within CD8(+) cells was decreased in the postexercise period compared with values obtained immediately after exercise, whereas the expression of IL-2 and IL-4 did not change within the CD4(+) and CD8(+) cell populations. The decrease in IFN-gamma-producing CD8(+) T cells postexercise was negatively correlated with a decrease in percentage of memory T cells within the CD8(+) cells (r = -0.94; P < or = 0.002). In conclusion, this study demonstrates that the exercise-induced change in type 1 cytokine-producing T cells is related to a decline in memory cells.     

Dysfunction of simian immunodeficiency virus/simian human immunodeficiency virus-induced IL-2 expression by central memory CD4+ T lymphocytes

Production of IL-2 and IFN-gamma by CD4+ T lymphocytes is important for the maintenance of a functional immune system in infected individuals. In the present study, we assessed the cytokine production profiles of functionally distinct subsets of CD4+ T lymphocytes in rhesus monkeys infected with pathogenic or attenuated SIV/simian human immunodeficiency virus (SHIV) isolates, and these responses were compared with those in vaccinated monkeys that were protected from immunodeficiency following pathogenic SHIV challenge. We observed that preserved central memory CD4+ T lymphocyte production of SIV/SHIV-induced IL-2 was associated with disease protection following primate lentivirus infection. Persisting clinical protection in vaccinated and challenged monkeys is thus correlated with a preserved capacity of the peripheral blood central memory CD4+ T cells to express this important immunomodulatory cytokine.     

Effects of beta-arrestin 2 on cytokine production of CD4+ T lymphocytes of mice with allergic asthma

Beta-arrestin 2 has been shown to participate in the pathogenesis of asthma by inducing Th2 cell migration to the lungs. Whether beta-arrestin 2 regulates cytokine production of CD4+ T cells is still unknown. The aim of the present study was to investigate the effect of beta-arrestin 2 on the cytokine production of CD4+ T lymphocytes and the mechanism involved in a mouse model for asthma. After silencing beta-arrestin 2 expression in CD4+ T lymphocytes from asthmatic mice by RNA interference (RNAi), the interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) levels in CD4+ T lymphocyte culture supernatants with or without terbutaline stimulation were determined. Cell-surface beta2 adrenergic receptor (beta2AR) as well as GATA3 expression of CD4+ T lymphocytes were also measured. CD4+ T lymphocytes of mice with allergic asthma expressed higher levels of beta-arrestin 2 on both mRNA and protein levels. beta-arrestin 2 RNAi decreased IL-4 (43.16%) and GATA3 (protein 77.21%, mRNA 62.98%) expression after terbutaline stimulation. Cell-surface beta2AR of CD4+ T lymphocytes decreased (15.27%) after terbutaline treatment, but recovered after beta-arrestin 2 RNAi down-modulation. These findings demonstrate that beta-arrestin 2 regulates IL-4 production and GATA3 expression of CD4+ T lymphocytes partly through the beta2AR signaling pathway in an allergic asthma model.     

IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer.

Vaccinations with tumor cells engineered to produce IL-4 prolonged survival and cured 30% of mice bearing pulmonary metastases, an effect abrogated by in vivo depletion of T cells. Vaccination induced type 2 T cell polarization in both CD4 and CD8 T lymphocyte subsets. We focused on the antitumor activity exerted by type 2 CD8+ T cells (Tc2) activated by IL-4 tumor cell vaccination. Tc2 lymphocytes lacked in vitro tumor cytotoxicity, but released IL-4 upon stimulation with tumor cells, as shown by limiting dilution analysis of the frequencies of tumor-specific pCTL and of CD8 cells producing the cytokine. In vivo fresh purified CD8+ T lymphocytes from IL-4-vaccinated mice eliminated 80-100% of lung metastases when transferred into tumor-bearing mice. CD8+ lymphocytes from IL-4-vaccinated IFN-gamma knockout (KO), but not from IL-4 KO, mice cured lung metastases, thus indicating that IL-4 produced by Tc2 cells was instrumental for tumor rejection. The antitumor effect of adoptively transferred Tc2 lymphocytes needed host CD8 T cells and AsGM1 leukocyte populations, and partially granulocytes. These data indicate that Tc2 CD8+ T cells exert immunoregulatory functions and induce tumor rejection through the cooperation of bystander lymphoid effector cells. Tumor eradication is thus not restricted to a type 1 response, but can also be mediated by a type 2 biased T cell response.     

IFN-gamma and CD8+ T cells restore host defenses against Pneumocystis carinii in mice depleted of CD4+ T cells

Host defenses against infection are profoundly compromised in HIV-infected hosts due to progressive depletion of CD4+ T lymphocytes and defective cell-mediated immunity. Although recent advances in antiretroviral therapy can dramatically lower HIV viral load, blood CD4+ T lymphocytes are not restored to normal levels. Therefore, we investigated mechanisms of host defense other than those involving CD4+ T lymphocytes against a common HIV-related opportunistic infection, Pneumocystis carinii (PC) pneumonia. Using CD4-depleted mice, which are permissive for chronic PC infection, we show that up-regulation of murine IFN-gamma by gene transfer into the lung tissue results in clearance of PC from the lungs in the absence of CD4+ lymphocytes. This resolution of infection was associated with a >4-fold increase in recruited CD8+ T lymphocytes and NK cells into the lungs. The role of CD8+ T cells as effector cells in this model was further confirmed by a lack of an effect of IFN-gamma gene transfer in scid mice or mice depleted of both CD4+ and CD8+ T cells. Cytokine mRNA analysis revealed that recruited, lung-derived CD8+ T cells had greater expression of IFN-gamma message in animals treated with the IFN-gamma gene. These results indicate that CD8+ T cells are capable of clearing PC pneumonia in the absence of CD4+ T cells and that this host defense function of CD8+ T cells, as well as their cytokine repertoire, can be up-regulated through cytokine gene transfer.     

Expression and function of PDCD1 at the human maternal-fetal interface

The failure to reject the semiallogenic fetus by maternal T lymphocytes suggests that potent mechanisms regulate these cells. PDCD1 is a CD28 family receptor expressed by T cells, and its ligand CD274 is strongly expressed by trophoblast cells of the human placenta. In this study, we examined whether human maternal T cells express PDCD1. Immunofluorescence examination of uterine tissues revealed PDCD1 expression on CD3+ cells was low in nonpregnant endometrium but increased in first-trimester decidua and remained elevated in term decidua (P < 0.05). In addition, higher relative proportions of term decidual CD8 bright, CD4+, and regulatory T cells expressed PDCD1 in comparison to autologous peripheral blood (P < 0.05). Term decidual T cells also expressed full-length and soluble PDCD1 mRNA isoforms more abundantly than their peripheral blood counterparts (P 相似文献   

Salivary gland extract from Ixodes ricinus tick polarizes the cytokine profile toward Th2 and suppresses proliferation of T lymphocytes in human PBMC culture.

Tick salivary gland extract (SGE) was previously shown to inhibit murine T cell proliferation. In mice, SGE has an inhibitory effect on Th1 and a stimulatory effect on Th2 cytokine elaboration. In the present study, tick-mediated immunomodulation of human T cell proliferation and cytokine elaboration was analyzed using human peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A (Con A) or lipopolysaccharide (LPS). Using flow cytometry, tick saliva-induced changes were investigated in human mononuclear cell subpopulations. SGE from Ixodes ricinus dose-dependently inhibited human T cell proliferation. This finding supports the flow cytometry data, showing that the percentage of Con A-activated HLA-DR-CD3+ T lymphocytes and CD4+ CD8+ double-positive T cells decreased after SGE treatment. SGE significantly inhibited the in vitro production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) secreted by Th1 lymphocytes. In contrast, the elaboration of IL-4, IL-6, and IL-10 secreted by Th2 lymphocytes was significantly stimulated by I. ricinus SGE. Similarly, the production of both IL-1alpha and IL-1beta was significantly stimulated after SGE treatment. These data indicate that the tick-induced immunomodulatory events in humans are similar to those previously described in a murine model.     

Human leptin enhances activation and proliferation of human circulating T lymphocytes

Leptin is an adipocyte-secreted hormone that centrally regulates weight control. However, leptin receptor is expressed not only in the central nervous system, but also in other systems such as reproductive and hematopoietic tissues. Human leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages and human circulating monocytes. In this paper we have assessed the presence of leptin receptors in peripheral human T lymphocytes and we have studied their functional role. Both CD4(+) and CD8(+) T lymphocytes express leptin receptors. Moreover, we show that human leptin dose-dependently enhances proliferation and activation of human circulating T lymphocytes when they are costimulated by PHA or Con A. Leptin alone was not able to activate T lymphocytes. To confirm a direct effect of leptin on T lymphocytes, monocytes were extracted by adhesion to culture flasks. The early activation surface marker CD69 was then induced in both CD4(+) and CD8(+) T lymphocytes after 8 h stimulation with PHA or Con A. Leptin dose-dependently enhanced stimulated CD69 expression. Moreover, leptin dose-dependently enhanced the expression of the late activation markers CD25 and CD71 in both CD4(+) and CD8(+) T lymphocytes after 48 h stimulation with PHA or Con A. Finally, we have found that leptin modulates CD4(+) T lymphocyte activation toward Th1 phenotype by stimulating the synthesis of IL-2 and IFN-gamma. These results demonstrate the presence of the leptin receptor in human circulating CD4(+) and CD8(+) T lymphocytes and a functional role of leptin as a modulator (enhancer) of lymphocyte stimulation with a shift toward Th1 cytokine-production profile. This function of leptin may have some relevance in the pathophysiology of immunologic alterations related to obesity.     

Mouse CD8+ CD122+ T cells with intermediate TCR increasing with age provide a source of early IFN-gamma production

Although CD8+ IL-2Rbeta (CD122)+ T cells with intermediate TCR reportedly develop extrathymically, their functions still remain largely unknown. In the present study, we characterized the function of CD8+ CD122+ T cells with intermediate TCR of C57BL/6 mice. The proportion of CD8+ CD122+ T cells in splenocytes gradually increased with age, whereas CD8+ IL-2Rbeta-negative or -low (CD122-) T cells conversely decreased. The IFN-gamma production from splenocytes stimulated with immobilized anti-CD3 Ab in vitro increased with age, whereas the IL-4 production decreased. When sorted CD8+ CD122+ T cells were stimulated in vitro by the anti-CD3 Ab, they promptly produced a much larger amount of IFN-gamma than did CD8+ CD122- T cells or CD4+ T cells, whereas only CD4+ T cells produced IL-4. The depletion of CD8+ CD122+ T cells from whole splenocytes greatly decreased the CD3-stimulated IFN-gamma production and increased the IL-4 production, whereas the addition of sorted CD8+ CD122+ T cells to CD8+ CD122+ T cell-depleted splenocytes restored the IFN-gamma production and partially decreased IL-4 production. It is of interest that CD8+ CD122+ T cells stimulated CD4+ T cells to produce IFN-gamma. The CD3-stimulated IFN-gamma production from each T cell subset was augmented by macrophages. Furthermore, CD3-stimulated CD8+ CD122+ T cells produced an even greater amount of IFN-gamma than did liver NK1.1+ T cells and also showed antitumor cytotoxicity. These results show that CD8+ CD122+ T cells may thus be an important source of early IFN-gamma production and are suggested to be involved in the immunological changes with aging.     

Chemokine monokine induced by IFN-gamma/CXC chemokine ligand 9 stimulates T lymphocyte proliferation and effector cytokine production

Monokine induced by IFN-gamma (MIG; CXC chemokine ligand (CXCL)9) is important in T lymphocyte recruitment in organ transplantation. However, it is not known whether this chemokine, in addition to its chemotactic properties, exerts any effect on T lymphocyte effector functions. For in vivo studies, we used a previously characterized murine model of chronic rejection. The recipient mice were treated with anti-MIG/CXCL9 Ab; graft-infiltrating cells were analyzed for IFN-gamma production. For in vitro studies, exogenous CXCR3 ligands were added to CD4 lymphocytes in MLRs, and the proliferative responses were measured. Separate experiments quantitated the number of IFN-gamma-producing cells in MLRs by ELISPOT. Neutralization of MIG/CXCL9, in the in vivo model, resulted in significant reduction in the percentage of IFN-gamma-producing graft-infiltrating T lymphocytes. In vitro experiments demonstrated that 1) exogenous MIG/CXCL9 stimulated CD4 lymphocyte proliferation in a MHC class II-mismatched MLR, 2) MIG/CXCL9 also increased the number of IFN-gamma-producing CD4 lymphocytes in ELISPOT, 3) neutralization of MIG/CXCL9 in MLR reduced T lymphocyte proliferation, 4) IFN-gamma-inducible protein 10/CXCL10 and IFN-inducible T cell alpha chemoattractant/CXCL11 had similar effects on T lymphocyte proliferation, 5) MIG/CXCL9 stimulated T lymphocyte proliferation in MHC class I- and total MHC-mismatched MLRs, 6) neutralization of CXCR3 reduced MIG/CXCL9-induced T lymphocyte proliferation and the number of IFN-gamma-positive spots on ELISPOT, and 7) the proliferative effects of MIG/CXCL9 were mediated via an IL-2-independent pathway and were controlled by IFN-gamma. This study demonstrates that MIG/CXCL9 stimulates T lymphocyte proliferation and effector cytokine production, in addition to its chemotactic effects. This novel observation expands our current understanding of MIG/CXCL9 biology beyond that of mediating T cell trafficking.     

Orally administered Kampo (Japanese herbal) medicine, "Juzen-Taiho-To" modulates cytokine secretion in gut associated lymphoreticular tissues in mice.

The influence of the oral administration of Juzen-Taiho-To (JTT; Si-Quan-Da-Bu-Tang in Chinese), a Kampo (Japanese herbal) medicine, on the cytokine production in mice were investigated. Lymphocytes from spleen (SPN), mesenteric lymph node (MLN) and Peyer's patches (PP) from mice, which received orally administered JTT for 2 weeks, were stimulated with concanavalin A (Con A), and the resulting conditioned medium was tested for cytokine production by ELISA. Administration of JTT caused enhancement of interferon g (IFN-gamma) and interleukin-4 (IL-4) production to some extent but decreased IL-5 production from the SPN. On the other hand, notable changes in cytokine production were observed in lymphocytes from MLN and PP. Administration of JTT increased IFN-gamma production remarkably, as well as IL-5 secretion from both MLN and PP, whereas IL-2 secretion was plainly reduced. The ratio of IFN-gamma and IL-4 was shifted to Th1 dominant in MLN and PP, however changed little in SPN. The flow cytometric analysis revealed that the population of CD3+, CD4+, CD45R/B220+, and CD45RBlowCD4+ cells in each lymphocyte was not changed significantly after oral administration of JTT. These findings demonstrate that the lymphocytes from gut associated lymphoreticular tissues (GALT) are more sensitive to produce cytokines on cytokine production than those from SPN by oral administration of JTT, and that the modulation of cytokine production may be due to functional change of lymphocytes but not change in lymphocytes population.     

Selective expansion and partial activation of human NK cells and NK receptor-positive T cells by IL-2 and IL-15.

IL-2 and IL-15 are lymphocyte growth factors produced by different cell types with overlapping functions in immune responses. Both cytokines costimulate lymphocyte proliferation and activation, while IL-15 additionally promotes the development and survival of NK cells, NKT cells, and intraepithelial lymphocytes. We have investigated the effects of IL-2 and IL-15 on proliferation, cytotoxicity, and cytokine secretion by human PBMC subpopulations in vitro. Both cytokines selectively induced the proliferation of NK cells and CD56(+) T cells, but not CD56(-) lymphocytes. All NK and CD56(+) T cell subpopulations tested (CD4(+), CD8(+), CD4(-)CD8(-), alphabetaTCR(+), gammadeltaTCR(+), CD16(+), CD161(+), CD158a(+), CD158b(+), KIR3DL1(+), and CD94(+)) expanded in response to both cytokines, whereas all CD56(-) cell subpopulations did not. Therefore, previously reported IL-15-induced gammadelta and CD8(+) T cell expansions reflect proliferations of NK and CD56(+) T cells that most frequently express these phenotypes. IL-15 also expanded CD8alpha(+)beta(-) and Valpha24Vbeta11 TCR(+) T cells. Both cytokines stimulated cytotoxicity by NK and CD56(+) T cells against K562 targets, but not the production of IFN-gamma, TNF-alpha, IL-2, or IL-4. However, they augmented cytokine production in response to phorbol ester stimulation or CD3 cross-linking by inducing the proliferation of NK cells and CD56(+) T cells that produce these cytokines at greater frequencies than other T cells. These results indicate that IL-2 and IL-15 act at different stages of the immune response by expanding and partially activating NK receptor-positive lymphocytes, but, on their own, do not influence the Th1/Th2 balance of adaptive immune responses.     

Novel function for intestinal intraepithelial lymphocytes. Murine CD3+, gamma/delta TCR+ T cells produce IFN-gamma and IL-5.

Intestinal intraepithelial lymphocytes (IEL) from mice are greater than 80% CD3+ T cells and could be separated into four subsets according to expression of CD4 and CD8. In our studies designed to assess the functions of IEL, namely, cytokine production, it was important to initially characterize the various subsets of T cells that reside in IEL. The major subset was CD4-, CD8+ (75% of CD3+ T cells), which contained approximately 45 to 65% gamma/delta TCR+ and 35 to 45% alpha/beta TCR+ T cells. Approximately 7.5% of IEL T cells were CD4-, CD8- (double negative) and gamma/delta+ population. On the other hand, CD4+, CD8+ (double positive) and CD4+, CD8- fractions represented 10% and 7.5% of CD3+ T cells, respectively, which were all alpha/beta TCR+. Inasmuch as CD3+, CD4-, CD8+ T cells are a major subset of IEL which contain both gamma/delta TCR or alpha/beta TCR-bearing cells, the present study was focused on the capability of this subset of IEL T cells to produce the cytokines IFN-gamma and IL-5. Both gamma/delta TCR+ and alpha/beta TCR+ IEL spontaneously produced IFN-gamma and IL-5, although higher frequencies of cytokine spot-forming cells were associated with the alpha/beta TCR+ subset. Approximately 30% of CD8+, gamma/delta TCR+ cells produced both cytokines, whereas approximately 90% of alpha/beta TCR+ T cells produced either IFN-gamma or IL-5. Both gamma/delta TCR+ and alpha/beta TCR+ IEL possessed large quantities of cytokine-specific mRNA, clearly showing that these IEL were programmed for cytokine production. When IEL were activated with anti-gamma/delta or anti-CD8 antibodies, higher numbers of IFN-gamma and IL-5 spot-forming cells were noted. The present study has provided direct evidence that a major function of IEL involves cytokine production, and this is the first evidence that gamma/delta TCR+ cells in IEL possess the capability of producing both IL-5 and IFN-gamma.     

Role of T cell subsets in the modulation of Mycobacterium avium growth within human monocytes

Mycobacterium avium frequently causes disseminated disease in patients with advanced AIDS with low CD4 counts. The effects of T lymphocyte on intracellular M. avium replication were examined. Plastic adherent monocytes and nonadherent lymphocytes were separated from peripheral blood mononuclear cells. After infection with M. avium, monocytes were cultured with or without autologous lymphocytes (1-10 cells/monocyte) for up to 7 days. Addition of lymphocytes to M. avium-infected monocytes significantly decreased intracellular M. avium growth after 7 days culture (n = 11, P < 0.01, paired t test) and increased IFN-gamma production compared to monocytes alone. Neutralizing IFN-gamma partially abrogated lymphocyte activity. CD4 depletion diminished anti-mycobactericidal effects and CD8(+) lymphocytes increased intracellular M. avium growth (P < 0.05, n = 5, t test). These data suggest that interactions between monocytes and nonadherent cell fractions such as CD4(+) T cells and NK cells are important in intracellular M. avium growth modulation in monocytes from healthy humans.     

Proteoglycan isolated from Phellinus linteus inhibits tumor growth through mechanisms leading to an activation of CD11c+CD8+ DC and type I helper T cell-dominant immune state

Dendritic cells (DC) are known to not only induce the activation of T cells, but are also associated with the polarization of T cells. This study investigated whether or not proteoglycan (PG) isolated from Phellinus linteus induces the phenotypic and functional maturation of CD11c+ DC in vitro and in vivo. PG was found to induce the phenotypic and functional maturation of bone marrow-derived DC via Toll-like receptors (TLR) 2 and 4 in vitro. Administration of PG in vivo strongly inhibited the MCA-102 tumor growth and increase in vivo. The ratio of CD8+ DC to CD8- DC increased, and PG enhanced IL-12 and IFN-gamma production, and expression of surface molecules including major histocompatibility complexes (MHC) classes I, MHC II, CD80, and CD86 in MCA-102-challenged mice. PG also caused a marked increase in the production of Th (helper T cells)-1 cytokine (IFN-gamma) and a decrease in the production of Th-2 cytokine (IL-4) by splenic cells and inguinal lymph node cells in MCA-102 tumor-bearing mice. Furthermore, PG stimulated the proliferation of CD4+ and CD8+ T cells. In addition, a combination of PG and tumor lysate-pulsed DC inhibited completely the growth of MCA-102 cells in tumor-bearing mice. These results indicate that the administration of PG inhibited the tumor growth through a mechanism leading to a Th-1 dominant immune state and the activation of CD11cCD8+ DC.     

Beta-adrenergic receptor blockade during exercise decreases intestinal lymphocyte apoptosis but not cell loss in mice

Catecholamines induce apoptosis in various lymphoid populations. This process can occur with both alpha- and beta-adrenoreceptors. Heavy exercise increases plasma catecholamine concentrations, and is also a cause of lymphocyte apoptosis, a possible explanation for postexercise lymphocytopenia. The purpose of this study was to examine the effects of adrenoreceptor antagonism on exercise-induced decreases and apoptosis of intestinal lymphocytes. Mice received an intraperitoneal injection of phentolamine (a nonselective alpha-blocker), nadolol (a nonselective beta-blocker), or saline (vehicle) prior to an exhaustive bout of exercise. Total intestinal lymphocyte numbers, percent and number of CD3+ lymphocytes, and cell viability were assessed. Neither alpha- nor beta-antagonism prevented exercise-induced cell loss in the intestine; however, pretreatment with nadolol significantly reduced the number of apoptotic and necrotic cells. Phentolamine administration appeared to increase the incidence of cell death among intestinal lymphocytes. Both drugs decreased the percentage of CD3+ intestinal lymphocytes. Our study suggests that catecholamines are not responsible for postexercise lymphocytopenia, but beta-adrenoceptor blockade may confer protection against exercise-induced apoptosis of intestinal lymphocytes.