Cytokine production in children with tuberculous infection and disease.

To determine if the manifestations of initial infection with Mycobacterium tuberculosis reflect changes in the balance of T cell cytokines, we evaluated cytokine production by M. tuberculosis-stimulated peripheral blood mononuclear cells (PBMCs) from 24 children with tuberculosis and 22 children who were healthy tuberculin reactors. PBMCs from patients with tuberculosis had lower production and mRNA expression of interferon gamma (IFN-gamma) than did PBMCs from healthy tuberculin reactors. IFN-gamma production was most severely depressed in patients with moderately advanced and far-advanced pulmonary disease and in malnourished patients. Production of IL-12, IL-4, and IL-10 was similar in tuberculosis patients and healthy tuberculin reactors. These results indicate that, during the initial immune response to M. tuberculosis, development of tuberculosis is associated with diminished IFN-gamma production, which is not due to reduced production of IL-12 or enhanced production of IL-4 or IL-10.     

Increased proportions of peripheral blood gamma delta T cells in patients with pulmonary tuberculosis.

There is a small population of peripheral T cells bearing the gamma delta T-cell receptor, which may be involved in the defense against invading microorganisms and tumor cells. The present study was designed to evaluate the levels of gamma delta T cells in patients with pulmonary tuberculosis, bacterial pneumonia, chronic lower respiratory tract infection, lung cancer, and normal control subjects with or without old tuberculous lesion. The results showed that only patients with tuberculosis had significantly increased proportions of peripheral blood gamma delta T cells. This study suggests that the increased proportions of gamma delta T cells in tuberculosis could be related to T-cell activation by Mycobacterium tuberculosis, although it remains to be investigated which components of mycobacteria are the major ligands for gamma delta T cells.     

Pleuritis as a manifestation of reactivation tuberculosis

PURPOSE: The purpose of this study was to determine the frequency with which tuberculous pleuritis is a manifestation of reactivation tuberculosis and to compare the clinical manifestations of reactivation tuberculous pleuritis with "classic" tuberculous pleuritis, in which chest roentgenograms reveal no parenchymal infiltrates. PATIENTS AND METHODS: We evaluated the medical records of 59 patients in whom tuberculous pleuritis was confirmed by histologic findings or mycobacterial culture. Twenty-seven patients (46%) had typical chest roentgenographic findings of reactivation tuberculosis, whereas 32 (54%) had classic tuberculous pleuritis. The clinical and laboratory features of these two groups were compared. RESULTS: Symptoms were more prolonged and pleural fluid glucose and lactate dehydrogenase concentrations were more markedly abnormal in patients with reactivation pleuritis than in those with classic pleuritis, suggesting a more chronic inflammatory process in the former group. Compared with patients with classic tuberculous pleuritis, those with reactivation pleuritis had a lower frequency of reactive tuberculin skin tests (61% versus 88%) and granulomatous pleural inflammation (25% versus 72%), but a higher bacillary burden, manifest by a higher frequency of positive sputum smears for acid-fast bacilli (50% versus 0%) and positive mycobacterial cultures from sputum (60% versus 23%) and pleural fluid (91% versus 66%). CONCLUSIONS: In contrast to previous reports, tuberculous pleuritis was a manifestation of reactivation tuberculosis in 46% (27 of 59) of patients. Tuberculous pleuritis is a more chronic process in patients with reactivation disease than in those with classic pleuritis. The lower frequency of reactive tuberculin skin tests and granuloma formation, combined with the higher bacillary burden in patients with reactivation pleuritis, suggest that these patients mount a less effective immune response to Mycobacterium tuberculosis infection than do patients with the classic form of tuberculous pleuritis.     

Clinical immunology of tuberculosis

The standard tuberculin skin test has been known as the prototype of delayed type hypersensitivity testing which is mediated by T cells and macrophages and plays an important role in the pathogenesis of tuberculosis. Tuberculosis is indeed a chronic infectious disease, but variation in the host immune responses to tubercle bacilli results in the various clinical manifestations of the disease ranging from an immunologically hyperreactive state observed in pleural fluid lymphocytes in tuberculous pleurisy to an almost totally unresponsive state observed in those severely ill with refractory tuberculosis. In tuberculous pleurisy, T cells in pleural fluid respond remarkably in vitro to PPD tuberculin whereas T cells in peripheral blood responded poorly to PPD stimulation. Compartmentalization of PPD-reactive T cells in the pleural fluid and immunosuppression by T cells and/or macrophages in the peripheral blood were responsible for this immunological difference observed between the lymphocytes in pleural fluid and those in peripheral blood of tuberculous pleurisy. In advanced, drug-resistant tuberculosis as well as in nontuberculous mycobacterial infection, the proliferative responses of T cells in vitro to PPD stimulation were impaired. This depressed T cell response was due to depressed interleukin-2 (IL-2) production and not due to depressed IL-2 responsiveness. Therefore, the addition of exogenous IL-2, returned the depressed PPD-induced lymphocyte proliferation in vitro in these patients to the level of the response observed in lymphocytes from patients with newly-diagnosed tuberculosis. Our results suggest that recombinant IL-2 offers a novel approach to the therapy of advanced, drug-resistant tuberculosis and nontuberculous mycobacterial infection. Preliminary clinical trials of immunotherapy with recombinant IL-2 reveals the effectiveness of this therapy and encourages us to extend the trial to a larger scale. Tubercle bacilli have various biological activities. Research on tuberculosis and tubercle bacilli have contributed much to the progress of biochemistry, pathology and immunology. Mycobacterium is a fascinating organism, which now presents another big appeal to those studying immunology: Study of immunological interaction between gamma delta T cells and the highly conserved protein in mycobacteria, HSP, heat shock protein will contribute to the elucidation of the mechanism of immunological surveillance and the mechanism of autoimmune diseases. In addition, it will also contribute to the development of a new mycobacterial vaccine which will give direct, protective immunity against tuberculosis.     

Dynamics of cytokine generation in patients with active pulmonary tuberculosis

PURPOSE OF REVIEW: Cytokines have been implicated in the protective immunity, pathophysiology and development of tuberculosis. Most people who become infected with Mycobacterium tuberculosis mount an effective protective immune response, but 5-10% develop disease. Active pulmonary tuberculosis can be considered to reflect an ineffective immune response against mycobacterial infection. A better understanding of how cytokine production contributes to immunity and pathology would aid the development of new vaccines and therapeutic strategies. RECENT FINDINGS: At the time of diagnosis, production of M. tuberculosis or mycobacterial antigen-induced interferon-gamma by peripheral blood mononuclear cells from tuberculosis patients is usually depressed, compared with that of healthy control subjects, whereas cytokine production at the site of disease is elevated. In most patients, depressed interferon-gamma production by peripheral blood mononuclear cells seems to be a transient response because it is significantly increased in most active tuberculosis patients during and following successful antituberculous therapy. However, some patients remain anergic in vivo and in vitro after chemotherapy, and the underlying biochemical mechanisms for T cell anergy in modulating protection or pathology in tuberculosis needs further clarification. Among the cytokines contributing to protective immunity, interleukins 12 and 18, and tumour necrosis factor-alpha are important, the basis of recent studies with tuberculosis patients. SUMMARY: A more complete understanding of cytokine dynamics in individual cells in active pulmonary tuberculosis patients will provide further knowledge about immunopathogenesis and protective immunity in human tuberculosis. This should ultimately enhance development of preventive and therapeutic strategies against this enormously successful intracellular pathogen.     

Analysis of tuberculin reaction of tuberculous children below 4 years of age]

To clarify whether the size of tuberculin reaction could be used as an useful index of the severity of tuberculosis, we analyzed the sizes of tuberculin reaction (TR) of 60 children below 4 years of age with active tuberculosis at the time of diagnosis. Of 60 patients, 53 (88.9%) had positive reactions to tuberculin. The mean size of TR of 60 patients was 24.0 +/- 13.9 mm and maximum size was 60 mm. Seven patients who had no reaction to the tuberculin skin test consisted of three primary complex and four serious tuberculosis (two miliary tuberculosis and two tuberculous meningitis). The patients without BCG vaccination showed significantly smaller TR than the patients with BCG vaccination (p < 0.05). The patients less than 1 year of age showed significantly smaller TR than the patients of 4 years of age (p < 0.05). The patients with serious tuberculosis showed significantly smaller TR than the patients with primary complex (p < 0.05). Of patients with primary complex, there were no difference of the size of TR between the patients with pulmonary tuberculosis (III) and hilar lymphadenopathy (H). Together with, it did not necessarily mean that negative TR showed no infection with tuberculosis and the sizes of TR depended on the severity of tuberculosis in infantis and young children.     

Update on tuberculous pleural effusion

The possibility of tuberculous pleuritis should be considered in every patient with an undiagnosed pleural effusion, for if this diagnosis is not made the patient will recover only to have a high likelihood of subsequently developing pulmonary or extrapulmonary tuberculosis Between 3% and 25% of patients with tuberculosis will have tuberculous pleuritis. The incidence of pleural tuberculosis is higher in patients who are HIV positive. Tuberculous pleuritis usually presents as an acute illness with fever, cough and pleuritic chest pain. The pleural fluid is an exudate that usually has predominantly lymphocytes. Pleural fluid cultures are positive for Mycobacterium tuberculosis in less than 40% and smears are virtually always negative. The easiest way to establish the diagnosis of tuberculous pleuritis in a patient with a lymphocytic pleural effusion is to generally demonstrate a pleural fluid adenosine deaminase level above 40 U/L. Lymphocytic exudates not due to tuberculosis almost always have adenosine deaminase levels below 40 U/L. Elevated pleural fluid levels of γ‐interferon also are virtually diagnostic of tuberculous pleuritis in patients with lymphocytic exudates. In questionable cases the diagnosis can be established by demonstrating granulomas or organisms on tissue specimens obtained via needle biopsy of the pleura or thoracoscopy. The chemotherapy for tuberculous pleuritis is the same as that for pulmonary tuberculosis.     

Vdelta2+ gammadelta T cell function in Mycobacterium tuberculosis- and HIV-1-positive patients in the United States and Uganda: application of a whole-blood assay

BACKGROUND: Vgamma9(+)Vdelta2(+) gammadelta T cells (Vdelta 2(+) T cells) are activated by Mycobacterium tuberculosis and secrete interferon (IFN)-gamma. Vdelta 2(+) T cells recognize phosphoantigens, such as bromohydrin pyrophosphate (BrHPP), and link innate and adaptive immunity. METHODS: A whole-blood assay was developed that used IFN-gamma secretion in response to BrHPP as a measurement of Vdelta2(+) T cell function. RESULTS: Peak IFN-gamma levels were detected after stimulating whole blood with BrHPP for 7-9 days. IFN- gamma production in whole blood in response to BrHPP paralleled IFN-gamma production and Vdelta2(+) T cell expansion of peripheral-blood mononuclear cells. The assay was used to evaluate Vdelta2(+) T cell function in subjects in the United States (n = 24) and Uganda (n = 178) who were or were not infected with M. tuberculosis and/or human immunodeficiency virus (HIV) type 1. When 50 micromol/L BrHPP was used, 100% of healthy subjects produced IFN-gamma. The Vdelta2(+) T cell response was independent of the tuberculin skin test response. In Uganda, Vdelta2(+) T cell responses were decreased in patients with tuberculosis (n = 73) compared with responses in household contacts (n = 105). HIV-1-positive household contacts had lower responses than did HIV-1-negative household contacts. HIV-1-positive patients with tuberculosis had the lowest V delta 2(+) T cell responses. CONCLUSIONS: Tuberculosis and HIV-1 infection are associated with decreased Velta2(+) T cell function. Decreased Vdelta2(+) T cell function may contribute to increased risk for tuberculosis in HIV-1-positive patients.     

Selective depression of interferon-gamma and granulysin production with increase of proliferative response by Vgamma9/Vdelta2 T cells in children with tuberculosis

Vgamma9/Vdelta2 T cells can contribute to protective immune response against Mycobacterium tuberculosis, although the extent to which and mechanisms by which they could actually protect against human tuberculosis remain unclear. We have previously reported that Vgamma9/Vdelta2 T cells from tuberculin purified protein derivative (PPD)-positive children, either healthy or affected by different clinical forms of tuberculosis, strongly proliferate to different phosphoantigens in vitro, whereas Vgamma9/Vdelta2 T cells from PPD-negative healthy subjects proliferate very poorly. We report here that Vgamma9/Vdelta2 T cells from tuberculous children have an increased proliferative activity, but decreased interferon (IFN)-gamma production and granulysin expression. After successful chemotherapy, the Vgamma9/Vdelta2 T cell proliferative response strongly decreased, whereas IFN-gamma and granulysin production consistently increased. Disease-associated changes in Vgamma9/Vdelta2 T cell effector functions in patients with tuberculosis are consistent with the possibility that these T cells may play a protective role in immune response against M. tuberculosis infection.     

Der tuberkulöse Pleuraerguss

Approximately one third of the world’s population is infected with Mycobacterium tuberculosis and among communicable diseases tuberculosis is the second leading cause of death. The most common type of tuberculosis is pulmonary tuberculosis. Among the extrapulmonary manifestations, tuberculous pleuritis ranks second only after lymphatic tuberculosis. Tuberculous pleuritis is most commonly a disease with acute onset which is self-limiting in the majority of cases. A large proportion of patients though develop some form of active tuberculosis after a latency period. Therefore the correct diagnosis and the initiation of treatment are of the utmost importance. The easiest way to establish the diagnosis of tuberculous pleuritis is to demonstrate an elevated ADA (adenosine deaminase) in a lymphocytic effusion. Should pleural fluid analysis be nondiagnostic, the diagnosis of tuberculous pleuritis can be established with percutaneous closed needle biopsy in over 80% of cases. All patients with an undiagnosed pleural effusion after closed needle biopsy require thoracoscopy with selected biopsies taken under direct vision. The diagnostic yield of thoracoscopy is close to 100% in tuberculous pleuritis.     

结核分枝杆菌γ-干扰素酶联免疫斑点试验在菌阴肺结核中的诊断价值

目的通过检测结核分枝杆菌γ-干扰素酶联免疫斑点试验的结果,探讨其在菌阴肺结核诊断及鉴别诊断中的意义。方法将研究对象分为菌阳肺结核、菌阴肺结核、肺部肿瘤、肺炎4组。所有患者分别进行结核分枝杆菌γ-干扰素酶联免疫斑点试验、结核抗体三项测定及结核菌素试验。结果菌阳肺结核、菌阴肺结核、肺部肿瘤、肺炎4组患者PPD试验阳性率为84.8%、83.3%、28.6%、33.3%;结核抗体试验的阳性率为84.8%、66.6%、28.6%、33.3%;ELISPOT试验阳性率为93.9%、93.3%、7.1%、3.3%。结论结核杆菌感染T细胞酶联免疫斑点试验在肺结核诊断,可能优于结核菌素试验及结核抗体测定,对于菌阴肺结核的诊断与鉴别诊断具有临床意义。     

Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens

Most cases of latent tuberculosis infection (LTBI) do not cause symptoms during the lifetime of the infected person. Longitudinal analysis of the immune response of healthy Mycobacterium tuberculosis-infected people might, therefore, give insight into the basis of protective immunity. In a longitudinal study, we documented the effect that treatment had on the T cell response to M. tuberculosis antigens in 33 healthy people with LTBI. Preventive treatment of LTBI resulted in a 1.8-fold average increase in the numbers of interferon (IFN)- gamma -producing T cells within 26 +/- 4 days (P = .006), followed by a decrease by the end of the treatment period (82 +/- 6 days; P = .004). There was no significant overall change in the T cell response to any antigen in a control group (n = 8) of patients who elected radiological follow-up. Using live M. tuberculosis strain H37Rv as a stimulant in an enzyme-linked immunospot assay in sensitized individuals, we showed that isoniazid, but not rifampin, led to an increase in the number of IFN- gamma -producing cells. These results suggest that the integrity of the bacterial cell wall is important for M. tuberculosis in avoiding immune recognition by T cells and favor a dynamic model of LTBI.     

New issues in tuberculosis

Tuberculosis remains a major health problem worldwide. The disease is caused by Mycobacterium tuberculosis whose preferred habitat is the host macrophage. The immune response against tuberculosis is mediated by different subsets of T cells including both conventional CD4 and CD8 T cells as well as unconventional CD1 restricted and gammadelta T cells. The CD1 restricted T cells are particularly remarkable because they recognise the glycolipids abundant in the mycobacterial cell wall. Although a vaccine, M.bovis BCG, is available which protects toddlers against miliary tuberculosis, it is ineffective in preventing pulmonary tuberculosis in adults. Therefore, a novel vaccine is urgently required. Knowledge about the functioning of different T cell populations during infection and disease provides the basis for rational vaccine design. We have constructed a recombinant BCG vaccine which, compared with wild-type BCG, induces superior protection not only against laboratory strains but also against clinical isolates of M. tuberculosis.     

The prevalence of pulmonary parenchymal tuberculosis in patients with tuberculous pleuritis

STUDY OBJECTIVE: To examine the prevalence and characteristics of parenchymal tuberculous pleuritis in adult patients. DESIGN: Prospective cohort study. SETTING: Three hospitals affiliated with Seoul National University in South Korea. PATIENTS: All patients > 15 years old with a diagnosis of tuberculous pleuritis were enrolled prospectively between January 1, 2004, and October 31, 2004. INTERVENTIONS: Diagnostic thoracocentesis and CT of the chest were done for each patient. Acid-fast bacilli (AFB) smears and cultures for Mycobacterium tuberculosis were requested if patients produced any sputum. A board-certified radiologist reviewed the chest radiographs for the presence and characteristics of any lesions. MEASUREMENTS AND RESULTS: One hundred six patients with tuberculous pleuritis were enrolled (median age, 53 years; range 16 to 89 years). Among them, 33 patients (31%) had sputum or bronchial washing findings positive for AFB smears or for M tuberculosis by culture. Lung parenchymal lesions were observed in 91 of the patients (86%) using chest CT; 39 patients (37%) with parenchymal lesions had radiographic characteristics of active pulmonary tuberculosis. In total, 62 patients (59%) had bacteriologically or radiographically active pulmonary tuberculosis. In addition, 78 patients (74%) had features of reactivated pulmonary tuberculosis. CONCLUSIONS: Lung parenchymal lesions were more common in this series of patients with tuberculous pleuritis than has been reported in previous studies. The patients mostly had radiographic features of reactivated, rather than primary, tuberculosis.     

Clinical presentation of tuberculosis and the degree of immunodeficiency in patients with HIV infection.

A retrospective study of 80 HIV patients diagnosed with tuberculosis was carried out in order to evaluate the clinical presentation of tuberculosis (CPT) in relation to the degree of HIV-induced immunodeficiency, as determined by the CD4 lymphocyte count and reactivity to the tuberculin and delayed-type hypersensitivity reaction (DHR) skin tests by applying 2TU of RT-23 tuberculin, and the Muiltest IMC Merieux, respectively. CPT classification was undertaken on the basis of the location of the disease: pulmonary tuberculosis (PT), distinguishing between typical pulmonary (TP) and atypical (AP) according to the radiological pattern; extrapulmonary (ET); mixed tuberculosis (MT) pulmonary and extrapulmonary; and miliary tuberculosis. The CD4 lymphocyte count was 264.6 +/- 226.8, the TP had the highest number (505), MT had 132 (p < 0.001) and the miliary tuberculosis had 148 (p < 0.001), the lowest. The tuberculin skin test was positive in 35%, of which 11% were MT (p < 0.05). In the delayed-type hypersensitivity reaction, 67% were non-normoergic, of which 95% and 100% were MT and miliary tuberculosis, respectively (p < 0.05). There was a good overlap between CD4 depletion and skin tests. TP exhibited moderate immunodeficiency, AP severe immunodeficiency, and mixed and miliary TB extremely high immunodeficiency.     

Differential cell analysis in bronchoalveolar lavage fluid from pulmonary lesions of patients with tuberculosis.

To obtain information on the cellular reactions to Mycobacterium (M) tuberculosis in the lung, we analyzed the cells in bronchoalveolar lavage (BAL) fluid from pulmonary lesions in comparison with those in BAL fluid from nonaffected regions of the lungs, and control lungs, and in peripheral blood of patients with tuberculosis. Neutrophils and lymphocytes were increased in number in BAL fluid from affected lesions of the lungs of patients with miliary tuberculosis and patients with active pulmonary tuberculosis compared with those in BAL fluid from control patients, but the number of alveolar macrophages was decreased in BAL fluid from tuberculous lesions. However, the numbers of these cells were not changed in the BAL fluid from nonaffected regions of the lungs of patients with active or inactive pulmonary tuberculosis. The numbers of lymphocytes were decreased and the numbers of monocytes were increased in peripheral blood from patients with miliary tuberculosis and with active tuberculosis, indicating inverse changes in the numbers of lymphocytes and monocytes in the peripheral blood to those in the BAL fluid of patients with tuberculosis. These results indicate characteristic redistributions of immune or inflammatory cells in response to infection with M tuberculosis and suggest that these changes are important for understanding the pathophysiology of pulmonary tuberculosis.     

Participation of gamma/delta-T cells in the protection against mycobacterial infection]

To search for a potential role of T cell receptor (TcR) gamma/delta T cells in host-defense against mycobacterial infection, we analyzed the kinetics, repertoire, specificity and function of gamma/delta T cells in the peritoneal cavity, lymph node (LN) and spleen during an intraperitoneal infection with a sublethal dose (5 x 10(5)) of viable BCG in mice. The number of bacteria in the organs increased to a maximal level by 28 days after infection, and thereafter decreased gradually. Of the CD3+ cells in PEC on day 7 after infection, approximately 25% were CD4-CD8-, most of which express TcR gamma/delta on their surface. On the other hand, the PEC on day 28 contained an increased number of alpha/beta T cells which were CD4+CD8- or CD4-CD8+ and the proportion of gamma/delta T cells was reciprocally decreased. The kinetics of gamma/delta and alpha/beta T cells in the LN ad spleen during BCG infection are much the same as that seen in the PEC. The early appearing gamma/delta T cells preferentially used V gamma 1/V delta 6 although the repertoire of these T cells are diversified. The gamma/delta T cells in PEC on day 7 remarkably proliferated and produced gamma IFN and IL-2 in response to sonicated BCG or PPD derived from Mycobacterium tuberculosis but not to 65 kd heat shock protein (HSP) derived from M. bovis. These results suggest that gamma/delta T cells precede alpha/beta T cells in appearance during mycobacterial infection and the early appearing gamma/delta T cells may participate in the protection at the early stage against the mycobacterial infection.     

Human in vitro immune responses to Mycobacterium tuberculosis.

SETTING: T helper cells can be divided into 2 subsets on the basis of their cytokine generation. T helper 1 cells secreting gamma interferon and interleukin 2 appear to be more prominent in patients with limited tuberculous disease. OBJECTIVE: The purpose of this study was to evaluate human T helper cell immune responses to mycobacterial antigens in vitro and correlate these with the clinical features of patients with tuberculous infection or disease. DESIGN: We studied 51 subjects and 11 controls who were grouped according to disease involvement as follows: 1) Mantoux negative, BCG negative, no disease; 2) Mantoux positive, no disease; 3) localized extrapulmonary; 4) healed pulmonary; 5) active pulmonary; and 6) miliary/disseminated. Peripheral blood mononuclear cells were cultured with PHA, PPD or Tetanus Toxoid, proliferation assessed and the supernatant analysed using an ELISA for IFN gamma. ELISA was also used to measure M. tuberculosis specific antibodies in the serum. RESULTS: Mantoux size correlated with PPD proliferation r = 0.5, P = 0.005 and gamma IFN production r = 0.36, P < 0.01. All groups produced abundant gamma IFN although there was a trend toward higher production in groups 3 and 4. M. tuberculosis specific IgA (P = 0.003) and IgG1 (P = 0.002) was higher in groups 5 and 6. Those patients with limited disease (groups 2-4) had significantly lower levels of IgG4 than patients with severe disease (groups 5 & 6) (P < 0.02). CONCLUSION: In conclusion patients with healed or extrapulmonary disease have immune responses in vitro suggestive of a TH1 (cell mediated immune) response, whereas patients with miliary/disseminated disease have antibody production suggestive of a TH2 response, together with high gamma IFN production. Both TH1 and TH2 responses may be necessary for host protection if there is a high bacillary load.     

Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis

We previously found that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) expand in response to Mycobacterium tuberculosis infection in individuals who are healthy tuberculin reactors, but not in tuberculin-negative individuals. We also found that the M. tuberculosis mannose-capped lipoarabinomannan and prostaglandin E2 produced by monocytes are involved in Treg expansion. In this study, we found that Tregs expanded from CD4(+)CCR4(+) cells but not from CCR4(-) cells. However, introduction of CCR4 small interfering RNA (siRNA) into CD4(+) cells only marginally reduced expansion of Tregs. Using siRNA and neutralizing antibodies, we found that expansion of Tregs by M. tuberculosis required expression of programmed death1 (PD-1) and expression of the signaling molecule, cytokine inducible SH2-containing protein (CISH). Anti-PD-1 siRNA inhibited expression of CISH by expanded Tregs. M. tuberculosis-expanded Tregs produced transforming growth factor β and interleukin 10 and reduced the frequency of interferon γ-producing autologous CD8(+) cells. We conclude that M. tuberculosis infection induces development of Tregs from CCR4(+) cells through a process that depends on PD-1and CISH.     

Regulation by innate immune T lymphocytes in the host defense against pulmonary infection with Cryptococcus neoformans

Recently, innate immune lymphocytes, such as natural killer (NK) T cells and gamma/delta antigen receptor-bearing T (gamma delta T) cells, have garnered much attention, and their biological significance in the tumor immunity, allergic diseases and infectious diseases is extensively exploited. We have addressed the role of these cells in the host defense using a mouse model of pulmonary infection with Cryptococcus neoformans, which frequently causes fatal meningoencephalitis in AIDS patients. Host defense to this fungal pathogen is largely mediated by cellular immunity, and type-1 helper T (Th1) cells play a central role in this process. This infection causes a prompt accumulation of both NKT and gamma delta T cells in the lung tissues in a monocyte chemoattractant protein (MCP)-1-dependent or -independent manner, respectively. Genetic deletion of V alpha 14+ NKT cells ameliorates the Th1 response and clearance of microorganisms in the lungs, whereas these host protective responses are rather enhanced in mice lacking gamma delta T cells. Thus, in some aspect, these innate immune lymphocytes may co-regulate the Th1-mediated response for induction of the moderate host defense. gamma delta T cells may act to keep the balance of Th1-Th2 responses in a proper manner by suppressing the exaggerated Th1 response caused by NKT cells. In this review, I describe the recent research development in the innate immune host defense against cryptococcal infection in respiratory organs with emphasis on our data in the regulatory role of NKT cells and gamma/delta T cells.