Increase in T‐Cell Subsets of Oral Mucosa: a Late Immune Response in Patients with Treated Coeliac Disease?*

BACKGROUND AND AIMS: In coeliac disease, the gut involvement is gluten-dependent. Following the introduction of a gluten-free diet, inflammatory cell infiltration decreases in the small intestinal mucosa. Our hypothesis was that the oral mucosa might mirror the changes found in coeliac disease similarly to the mucosa of the small intestine. Thus, the number of inflammatory cells in the oral mucosa would decrease in patients with coeliac disease on a gluten-free diet. METHODS: The distribution CD45RO+ and CD3(+) T cells, T-cell subpopulations (CD4(+), CD8(+), T-cell receptor (TCR)alpha beta+ and TCR gamma delta+ cells) and HLA DR expression were studied in the buccal mucosa of 15 untreated and 44 gluten-free diet treated coeliac disease patients, and of 19 controls. All 15 patients with untreated coeliac disease were immunglobulin (Ig)A endomysial antibody positive and all 44 patients on gluten-free diet except one were endomysial antibody negative, as were all control subjects. RESULTS: Untreated coeliac disease patients did not differ from controls in the densities of CD45RO+ cells, CD3(+) cells or of T-cell subsets. In contrast, in treated coeliac disease patients, a significant increase in the numbers of mast cells, CD3(+) and CD4(+) lymphocytes was found in the lamina propria of oral mucosa as compared with patients with untreated coeliac disease and controls. The increase in CD3(+) T cells was in part owing to an increase in lymphocytes expressing no TCR. No differences were found in the expression of human leucocyte antigen (HLA) DR in the epithelium or in the lamina propria in the patient groups studied or in the controls. In treated coeliac disease patients only a few TCR gamma delta+ T cells were found intraepithelially and in the lamina propria, but these cells were not detected in the lamina propria of oral mucosa of patients with untreated coeliac disease or in the controls. CONCLUSIONS: The infiltration of T cells into oral mucosa was increased in treated coeliac disease patients in spite of adherence to a gluten-free diet. Because the CD3(+) T cell count was higher than those of the TCR alpha beta+ and TCR gamma delta+ T cells, there must be other cells involved, probably natural killer (NK) cells. The increase in T-cell subsets in the treated coeliac disease patients seems not to result from poor dietary compliance, but might occur as a late immune response in coeliac disease and reflect chronic immunologic stimulation followed by regeneration of memory T cells.     

Decline in Immunological Responses Mediated by Dendritic Cells in Mice Treated with 18α-Glycyrrhetinic Acid

Objective: 18α-Glycyrrhetinic acid (18α-GA), a bioactive component of Glycyrrhiza glabra, has been shown in vitro immunomodulatory effects on dendritic cells (DCs). The aim of the present study is to evaluate the in vivo effect of 18α-GA on DCs and T cell responses.

Methods: 18α-GA was intraperitoneally administered to mice and splenic DCs were evaluated for expression of co-stimulatory molecules using flow cytometry. Isolated DCs were added to mixed lymphocyte reaction (MLR) and the proliferation of T cells was measured using BrdU assay. The level of IFN-γ in the MLR supernatant was determined by enzyme-linked immunosorbent assay. The in vivo effect of isolated DCs on antigen-specific delayed type hypersensitivity (DTH) response, and the number of regulatory T (Treg) cells in mice spleen by flow cytometry, were investigated.

Results: DCs isolated from 18α-GA-treated mice expressed lower levels of CD40 (p < 0.05) and MHC II (p < 0.01) compared to those of control group. In MLR assay isolated DCs decreased T cell proliferation to 83.54% ± 4.3% of control (p < 0.05). The level of IFN-γ in the MLR supernatant was declined to 25.2% ± 6.8% of control. In DTH test, DCs isolated from 18α-GA-treated mice significantly suppressed antigen-specific cell mediated immune response (3.3 ± 1 mm in test group versus 6.5 ± 1.2 mm in control group, ρ < 0.01). The percentage of Treg cells in spleen of 18α-GA-treated mice (6.37% ± 2.3%) was lower than that of control group (13.85% ± 0.4%, ρ < 0.05).

Conclusions: In vivo administration of 18α-GA resulted in inhibition of DCs maturation and T cell-mediated responses, the effects that may candidate this compound for its possible benefits in immune-mediated diseases.     

CD4+LAP+ and CD4+CD25+Foxp3+ Regulatory T Cells Induced by Nasal Oxidized Low-Density Lipoprotein Suppress Effector T Cells Response and Attenuate Atherosclerosis in ApoE−/− Mice

Increasing studies have demonstrated that atherosclerosis is a chronic immunoinflammatory disease, and that oxidized low-density lipoprotein (oxLDL)-specific T cells contribute to the autoimmune process in atherosclerosis. Oral administration of oxLDL, which was identified as a candidate autoantigen in atherosclerosis, was shown to induce tolerance and suppress atherogenesis. However, the precise mechanisms of mucosal tolerance induction, in particular nasal tolerance, remain unknown. In this study, we explored the effect of nasal oxLDL on atherosclerosis as well as the cellular and molecular mechanisms leading to atheroprotective responses, and then found that nasal oxLDL drastically ameliorate the initiation (47.6 %, p?p?=?0.001) of atherosclerosis. Most importantly, a significant 35.8 % reduction of the progression of atherosclerosis was observed in the enhanced immunization group (p?+ latency-associated peptide (LAP)⁺ regulatory T cells (Tregs) and CD4⁺CD25⁺Foxp3⁺ Tregs in spleens and cervical lymph nodes, together with increased transforming growth factor (TGF)-β production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-β in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-β was indispensable to CD4⁺LAP⁺ Tregs and CD4⁺CD25⁺Foxp3⁺ Tregs to acquire regulatory properties. Our studies suggest that CD4⁺LAP⁺ Tregs and CD4⁺CD25⁺Foxp3⁺ Tregs induced by nasal delivery of oxLDL can inhibit oxLDL-specific T cells response and ameliorate atherosclerosis process.     

Levels of Circulating Th17 Cells and Regulatory T Cells in Ankylosing Spondylitis Patients with an Inadequate Response to Anti−TNF-α Therapy

Purpose

To investigate the effects of TNF-α blockage on levels of circulating Th17, Treg and their related cytokines in ankylosing spondylitis (AS) patients with different response to anti-TNF-α therapy.

Methods

The frequencies of circulating Th17 and Treg and serum levels of related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 222 AS patients both before (baseline) and 6 months after anti-TNF-α therapy. Therapeutic response was defined according to ASAS (Assessment in Spondyloarthritis International Society) response criteria.

Results

Significantly higher baseline circulating Th17 and serum TNF-α, IL-6, IL-17, IL-23 were observed in active AS patients than in healthy controls. After anti-TNF-α therapy, 168 patients (75.7 %) were responders and 54 (24.3 %) were non-responders. Frequencies of Th17 significantly decreased in responders, but significantly increased in non-responders. Treg increased significantly in responders but decreased significantly in non-responders. Levels of TNF-α, IL-6, IL-17, and IL-23 were significantly decreased in responders. In contrast, IL-17 and IL-23 significantly increased in non-responders. TGF-β were significantly increased only in responders, whereas no significant changes were seen in IL-10 in either responders or non-responders. Spearman correlation analysis showed that frequencies of Th17 and levels of TNF-α, IL-6, IL-17, and IL-23 were positively correlated with BASDAI score. They were also positively correlated with BASFI score except for IL-6. Treg were found to be negatively correlated with BASDAI score.

Conclusions

The beneficial effect of anti-TNF-α therapy in AS might not only neutralize the effects of TNF-α but also down-regulate Th17 and Th17-related cytokines accompanied by up-regulating the Treg/TGF-β axis in responders.     

Assessment of Safety and the Immune Response to the CD4 “Internal Antigen” Mouse Anti-Idiotypic MAb 16D7 in Four Patients with SLE

We have analyzed the immune response elicited with the human CD4 internal antigen anti-idiotypic monoclonal antibody 16D7 in four patients with active systemic lupus erythematosus and assessed the safety of the treatment. Patients 1 and 2 received three 2-mg 16D7 subcutaneous (SC) injections at 3-week intervals and mainly developed IgG1, whereas IgG1, IgG3, and IgG4 were detected in the sera of the other two patients (3 and 4) who received the same amount of 16D7 on days 0, 28, and 70. 16D7-F(ab`)<sub>2</sub> isotypic determinant-specific antibodies levels, evaluated by sera reactivity with the 16D7-isotype matched anti-idiotypic monoclonal antibody 14D6-F(ab`)₂, were low or undetectable in patient 1 and became detectable following the first and second boosters in patient 3 and patients 2 and 4, respectively. The highest level was seen in patients 3 and 4. The focusing pattern (spectrotype) of 16D7 idiotypic-specific antibodies suggested that multiple V genes are involved or many somatic mutations occur. Once established, each patients spectrotype remained stable. Although spectrotype were individually distinct, all four patients produced CD4-specific antibodies, indicating that this response crosses the genetic barrier. Disease relapsed after 11 (patient 2), 40 (patients 3 and 4), and 125 (patient 1) weeks. The lack of side effects and the prolonged periods of disease control (33 and 103 weeks after the last booster) warrants an extension of this study.     

Long-Term Effects of IFN-γ, IL-10, and TGF-β-Modulated Dendritic Cells on Immune Response in Lewis Rats

Increasing data have shown that IFN-, IL-10, and TGF--modulated dendritic cells (DC) provide a promising strategy in treatment of experimental allergic encephalomyelitis and experimental autoimmune myasthenia gravis through different manner. To explore the immune response status after long-term application of these cytokine-modulated-DC, Lewis rats were injected subcutaneously into naive DC and IFN-, IL-10, and TGF--modulated DC (i.e., IFN--DC, IL-10-DC, and TGF--DC) at does of 1 × 10⁶ cells/rat every month for continuous 18 months, respectively. No rats suffered from decreased vigor and activity as well as cachectic condition during 18-month observation, and no rats had body-weight loss after 18-month treatment. Exploratory laparectomy did not find any tumor in all rats. IL-10-DC and TGF--DC resulted in lower nonspecific (Con A-induced) and antigen specific (ovalbumin-stimulated) spleen mononuclear cells proliferation, accompanied by lower levels of IFN-, IL-10, and TNF-. On the contrary, IFN--DC did not suppress cell proliferation and IFN- and IL-10 production except only slightly decreased TNF- levels. These results suggest that IFN--DC seems to be a more ideal candidate in the treatment of autoimmune diseases without suppressing immune response.     

β-Galactomannan and Saccharomyces cerevisiae var. boulardii Modulate the Immune Response against Salmonella enterica Serovar Typhimurium in Porcine Intestinal Epithelial and Dendritic Cells

Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that causes inflammation, necrosis, and diarrhea in pigs, as well as being an important source of food-borne diseases in humans. Probiotics and prebiotics are promising alternatives to antibiotics to control and prevent intestinal infections. The present work investigated a recently developed β-galactomannan (βGM) prebiotic compared to the proven probiotic Saccharomyces cerevisiae var. boulardii on porcine ileum intestinal epithelial cells (IECs) of the IPI-2I line and monocyte-derived dendritic cells (DCs) cocultured in vitro with Salmonella. We observed that both S. cerevisiae var. boulardii and βGM inhibited the association of Salmonella with IECs in vitro. Our data indicated that βGM has a higher ability than S. cerevisiae var. boulardii to inhibit Salmonella-induced proinflammatory mRNA (cytokines tumor necrosis factor alpha [TNF-α], interleukin-1α [IL-1α], IL-6, and granulocyte-macrophage colony-stimulating factor [GM-CSF] and chemokines CCL2, CCL20, and CXCL8) and at protein levels (IL-6 and CXCL8). Additionally, βGM and S. cerevisiae var. boulardii induced some effects on DCs that were not observed on IECs: βGM and S. cerevisiae var. boulardii showed slight upregulation of mRNA for TNF-α, GM-CSF, and CCR7 receptor on porcine monocyte-derived dendritic cells (DCs). Indeed, the addition of βGM or S. cerevisiae var. boulardii on DCs cocultured with Salmonella showed higher gene expression (mRNA) for TNF-α, GM-CSF, and CXCL8 compared to that of the control with Salmonella. In conclusion, the addition of βGM inhibits Salmonella-induced proinflammatory profiles in IECs but may promote DC activation, although associated molecular mechanisms remain to be elucidated.     

IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host Disease

Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4⁺ forkhead box p3 (FoxP3⁺) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-γ⁺ CD4⁺ T cells. However, IFN-γ is pro-apoptotic and IL-12-driven IFN-γ inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12^hi RAPA-DC would facilitate IFN-γ-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86^lo IL-12^hi cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4⁺ T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-γ neutralization or using T cells lacking the IFN-γ receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-γ were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40^−/− RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-γ. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4⁺ T cells induced by LPS-stimulated IL-12^hi RAPA-DC is mediated in vitro through IFN-γ and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-γ by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.     

Up-Regulation of ß1 Integrin on Tonsillar T Cells and its Induction by In Vitro Stimulation with α-streptococci in Patients with Pustulosis Palmaris et Plantaris

Pustulosis palmaris et plantaris (PPP) is a tonsil-related disease that can be cured with tonsillectomy. Recent immunological studies have shown that hyperactivation of tonsillar T cells is caused by a hyperimmune response to α-streptococci; recruitment of the T cells to lesions may be involved in the pathogenesis of PPP. ß1 integrin, expressed on T cells, not only provides a costimulatory signal for T-cell activation but also facilitates the accumulation of T cells in inflammatory skin lesions. In this study, we found that expression of ß1 integrin on both tonsillar and peripheral blood CD4-positive T cells was higher in PPP patients than in non-PPP patients. In vitro stimulation with α-streptococcal antigen significantly enhanced ß1 integrin expression on tonsillar CD4-positive T cells in PPP patients, but not in non-PPP patients. The chemotactic response of tonsillar CD4-positive T cells to vascular cell adhesion molecule-1, the ß1 integrin ligand, was significantly better in PPP patients than in non-PPP patients. The percentage of ß1 integrin-positive peripheral blood CD4-positive T cells decreased after tonsillectomy in PPP patients. The numbers of ß1 integrin-positive T cells and the expression of vascular cell adhesion molecule-1 were more elevated in plantar PPP skin lesions than in normal skin. These results suggest that ß1 integrin may play a key role in the pathogenesis of PPP.     

Oligoclonal CD8+ T-Cell Expansion in Patients with Chronic Hepatitis C Is Associated with Liver Pathology and Poor Response to Interferon-α Therapy

The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.     

CCR7+ Central and CCR7− Effector Memory CD4+ T Cells in Human Cutaneous Leishmaniasis

Purpose

The profile of central (=T_CM) and effector (=T_EM) memory CD4⁺ T cell subsets and the possible role as surrogate markers of protection is studied in the volunteers with history of cutaneous leishmaniasis (HCL).

Methods

Profile of T cell subsets based on CCR7/CD45RA expressions and phenotypic changes after soluble Leishmania antigen (SLA) stimulation were analyzed. Then, sorted CD4⁺CD45RO^?CD45RA⁺ naïve T, CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM, CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM subsets were cultured with SLA for proliferation, cytokine production and intracellular cytokine assays.

Results

In the HCL and control volunteers, the mean frequencies of CD4⁺CD45RA⁺CCR7⁺ naïve T cells and CD4⁺CD45RA^?CCR7^? T_EM cells were higher than the other subsets before culture. Frequency of naïve T cells and CD4⁺CD45RA^?CCR7⁺ T_CM cells was significantly decreased (P?=?0.01 for naïve T and P?<?0.05 for T_CM cells) and frequency of T_EM cells was significantly increased after SLA stimulation compared to before culture (P?<?0.001). By CFSE labeling, CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM cells showed more proliferation potential than CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM cells. Stimulation of the T_EM cells in HCL volunteers induced a significantly higher IFN-γ production (P?=?0.04) with higher number of intracellular IFN-γ positive cells (P?=?0.032) than the same cells from controls. A significantly higher number of T_CM cells produced IL-2 in HCL volunteers compared with controls (P?<?0.05). Most of the intracellular IFN-γ positive T_EM cells were proliferating CFSE-dim populations (P?<?0.05).

Conclusions

A combination of Leishmania-reactive IFN-γ producing CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM and Leishmania-reactive IL-2 producing CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM are identified in individuals with history of CL which might play a role in protective recall immune response against Leishmania infection.     

Cross-Regulation of T Regulatory—Cell Response after Coxsackievirus B3 Infection by NKT and γδ T Cells in the Mouse

Coxsackievirus B3 (CVB3) variants H3 and H310A1 differ by a single nonconserved amino acid in the VP2 capsid region. C57Bl/6 mice infected with the H3 virus develop myocarditis correlating with activation of T cells expressing the Vγ4 T cell receptor chain. Infecting mice with H310A1 activates natural killer T (NKT; mCD1d-tetramer⁺ TCRβ⁺) cells, but not Vγ4 T cells, and fails to induce myocarditis. H310A1 infection preferentially activates M2 alternatively activated macrophage and CD4⁺FoxP3 (T regulatory) cells, whereas CD4⁺Th1 (IFN-γ⁺) cells are suppressed. By contrast, H3 virus infection activates M1 proinflammatory and CD4⁺Th1 cells, but not T regulatory cells. The M1 macrophage show significantly increased CD1d expression compared to M2 macrophage. The ability of NKT cells to suppress myocarditis was shown by adoptive transfer of purified NKT cells into H3-infected NKT knockout (Jα18 knockout) mice, which inhibited cardiac inflammation and increased T regulatory cell response. Cardiac virus titers were equivalent in all mouse strains indicating that neither Vγ4 nor NKT cells participate in control of virus infection. These data show that NKT and Vγ4 cells cross-regulate T regulatory cell responses during CVB3 infections and are the primary factor determining viral pathogenesis in this mouse model.Enteroviruses and adenoviruses cause approximately 80% of clinical viral myocarditis in all age groups.¹ Cardiac injury results from direct viral injury to infected myocytes and also from host immune responses triggered by the infection.² Host responses include: i) induction of proinflammatory cytokines [IL-6, IL-1β, and tumor necrosis factor-α (TNF-α)] that suppress myocardial cell contractility³; ii) lysis of infected cardiocytes⁴; and iii) humoral or cellular autoimmunity to heart antigens, leading to cardiocyte death or dysfunction.^5–7 T-cell depletion of mice infected with coxsackievirus B3 (CVB3) dramatically reduces animal mortality and cardiac inflammation,⁸ and heart-specific, autoimmune CD8⁺ T cells isolated from CVB3-infected mice⁹ transfer myocarditis into uninfected recipients. Furthermore, immunizing mice with cardiac myosin in adjuvant causes cardiac inflammation closely resembling the virus-induced disease.^7,10–12 Several studies demonstrate that induction of autoimmunity in myocarditis corresponds to a decrease in T regulatory cells,^13,14 and T regulatory 1 (Tr1) cells making IL-10 are the probable suppressive effectors causing myocarditis resistance in both myosin- and CVB3-induced disease.^12,15,16 Recently, studies have shown that γδ T cells activated during pathological CVB3 infections are primarily responsible for preventing T regulatory cell responses and directly kill differentiated CD4⁺CD25⁺FoxP3⁺ T regulatory cells through Fas-dependent mechanisms.^2,17Not all CVB3 variants cause myocarditis. Two CVB3 variants, H3 and H310A1, have been cloned and characterized. The H310A1 virus was isolated from the parental H3 virus using a monoclonal antibody to the viral receptor and has a single nonconserved mutation in the VP2 capsid protein in a puff region known for decay accelerating factor (DAF) binding.¹⁸ Unlike the highly myocarditic H3 virus, the H310A1 virus is amyocarditic and preferentially activates T regulatory cells¹⁶ due to an inability to stimulate γδ T cells during H310A1 virus infections.¹⁹ As shown here, although the γδ T cell response is defective in H310A1-infected mice, substantial numbers of natural killer T (NKT) cells are present in the hearts of H310A1-infected, but not H3-infected, animals. This raises the question whether NKT cells promote the generation of T regulatory cells in the myocarditis-resistant animals. This idea is supported by recent studies in which CVB3-infected mice given the NKT ligand, α-galactosylceramide (α-GalCer), develop significantly less myocarditis than untreated animals.²⁰ This study found alterations in cytokine environment in the α-GalCer–treated mice but did not investigate the role of T regulatory cells in causing the anti-inflammatory cytokine response.Although somewhat controversial, various reports indicate that NKT cells suppress autoimmunity or promote tolerance by their effect on T regulatory cell response. Interaction of antigen-presenting cells and NKT cells through CD1d during oral tolerance to nickel results in secretion of IL-4 and IL-10, and activation of T regulatory cells.^21–23 Similarly, systemic tolerance could not be established in a mouse model of anterior chamber–associated immune deviation in CD1d knockout (KO) mice unless the animals were transfused with NKT cells and CD1d⁺ antigen-presenting cells.²⁴ Other studies show that αGalCer, a well-known and specific NKT CD1d-restricted ligand, increases T regulatory cell numbers in vivo²⁵ and can suppress autoimmune diabetes in NOD mice.^26–28 Cytokines, such as transforming growth factor-β (TGF-β) and IL-10, can be produced by NKT cells,^29,30 which could affect dendritic cell cytokine (IL-10) and accessory molecule (CD40, CD80, and/or CD86) expression,^31–33 leading to T regulatory cell responses.^27,34 Here, studies show that NKT cells activated during H310A1 infection cause the increased T regulatory cell response seen in this model. These experiments show that the nature of the innate immune response following enterovirus infection is crucial in determining autoimmunity induction.     

Crucial Role of CD4+CD 25+ FOXP3+ T Regulatory Cell,Interferon-γ and Interleukin-16 in Malignant and Tuberculous Pleural Effusions

The differential diagnosis between malignant and tuberculous exudative pleural effusions is an important clinical problem. The aim of current study is to evaluate the frequencies of T-regulatory cells (Treg) on the basis of distinct phenotypes in the differential diagnosis between malignant and tuberculous pleural effusion. In addition, to evaluate Interferon-gamma (IFN- γ) and interleukin-16 (IL-16) levels and their correlation to Treg cells in malignant and tuberculous pleural effusions. Sixty patients with pleural effusion (26 tuberculous and 34 malignant) and 20 healthy controls were included in the study. Pleural fluid and peripheral blood were assessed for frequencies of T regs, IL-16, and IFN-γ. Pleural effusions from both tuberculous and malignant groups represented significantly higher levels (more in TB) for the following cell populations than peripheral blood: total lymphocytes, CD3+lymphocyte, CD4+CD25+lymphocyte and Treg (CD4+ CD25+FoxP3+). Levels of IL-16 and IFN-γ in tuberculous group were significantly higher than that in malignant group. Regulatory T cells, INF-γ and IL-16 are new important tools for differentiation between tuberculous and malignant pleural effusion.