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Background Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis and self-tolerance. The immune suppressive effects of Tregs should however be limited in case effective immunity is required against pathogens or cancer cells. We previously found that the Toll-like receptor 2 (TLR2) agonist, Pam3CysSK4, directly stimulated Tregs to expand and temporarily abrogate their suppressive capabilities. In this study, we evaluate the effect of Pam3CysSK4 and Legionella pneumophila , a natural TLR2 containing infectious agent, on effector T (Teff) cells and dendritic cells (DCs) individually and in co-cultures with Tregs. Results TLR2 agonists can directly provide a co-stimulatory signal inducing enhanced proliferation and cytokine production of naive CD4+ Teff cells. With respect to cytokine production, DCs appear to be most sensitive to low amounts of TLR agonists. Using wild type and TLR2-deficient cells in Treg suppression assays, we accordingly show that all cells (e.g. Treg, Teff cells and DCs) contributed to overcome Treg-mediated suppression of Teff cell proliferation. Furthermore, while TLR2-stimulated Tregs readily lost their ability to suppress Teff cell proliferation, cytokine production by Teff cells was still suppressed. Similar results were obtained upon stimulation with TLR2 ligand containing bacteria, Legionella pneumophila . Conclusions These findings indicate that both synthetic and natural TLR2 agonists affect DCs, Teff cells and Treg directly, resulting in multi-modal modulation of Treg-mediated suppression of Teff cells. Moreover, Treg-mediated suppression of Teff cell proliferation is functionally distinct from suppression of cytokine secretion.

Tregs play a central role in the suppression of immune reactions and prevention of autoimmune responses harmful to the host. During acute infection, however, Tregs might hinder effector T cell activity directed toward the elimination of the pathogenic challenge. Pathogen recognition receptors from the TLR family expressed by innate immune cells are crucial for the generation of effective immunity. We have recently shown the CD4CD25 Treg subset in TLR2 mice to be significantly reduced in number compared with WT littermate control mice, indicating a link between Tregs and TLR2. Here, we report that the TLR2 ligand Pam3Cys, but not LPS (TLR4) or CpG (TLR9), directly acts on purified Tregs in a MyD88-dependent fashion. Moreover, when combined with TCR stimulation, TLR2 triggering augmented Treg proliferation in vitro and in vivo and resulted in a temporal loss of the suppressive Treg phenotype in vitro by directly affecting Tregs. Importantly, WT Tregs adoptively transferred into TLR2 mice were neutralized by systemic administration of TLR2 ligand during the acute phase of a Candida albicans infection, resulting in a 100-fold reduced C. albicans outgrowth. This demonstrates that in vivo TLR2 also controls the function of Tregs and establishes a direct link between TLRs and the control of immune responses through Tregs.

The mechanisms of apoptosis have become better understood, in part with the discovery of Fas/ CD95. We report the case of a patient characterized by a decreased CD4+ T cell count and an overexpression of Fas/CD95 resulting in apoptosis. A 54-year-old man presented with disseminated Mycobacterium xenopi infection. Analysis showed CD4+ T lymphopenia. Tests for human immunodeficiency virus (HIV) types 1 and 2 were negative. We compared the patient with eight healthy controls and five HIV-infected patients in terms of the expression of Fas/CD95 and Fas-mediated apoptosis of peripheral T lymphocytes. The percent of CD95+ cells in lymphocytes was 98% for the patient, and the mean percent of CD95+cells in lymphocytes ± SD for HIV-infected patients and healthy controls was 75% ± 16% and 36% ± 26%, respectively. The patient had a high level of spontaneous apoptosis, and apoptotic cells were all identified as being CD4+ T cells. Monoclonal antibodies to CD95 dramatically increased apoptosis of CD4+ T cells exclusively. CD4+ T lymphopenia observed in our patient correlated with an overexpression of Fas together with spontaneous and Fas-induced apoptosis.

This prospective study investigated the contributions of apoptosis and proliferation of CD4+ T cells obtained by the introduction of a new antiretroviral treatment for human immunodeficiency virus infection. Virus load; T cell counts; apoptosis of T cell subsets, including naive cells; and proliferation were determined from treatment initiation to the third month in a cohort of patients. An increase in CD4+ T cell count ⩾100 cells/mL over baseline was considered to be a satisfactory immune reconstitution. Sixty-nine patients completed the protocol, 22 of whom met our definition of a satisfactory immune reconstitution, showing a significantly more pronounced reduction in spontaneous CD4+ T cell apoptosis at month 1 as well as month 3, compared with the other patients. In contrast, neither Fas-induced apoptosis down-regulation nor Fas-induced increased proliferation capacity was associated with a satisfactory immune reconstitution. Downregulation of CD4+ T cell apoptosis by antiretroviral treatment is the main mechanism associated with early CD4+ T cell increase.

To investigate whether stepwise selection of resistance mutations may mirror the continued bacterial exposure to antibiotics that occurs in the clinical setting. We examined the in vitro development of resistance to a number of commonly used antibiotics (cefepime, cefpirome, ceftazidime, cefotaxime, piperacillin and imipenem) in Pseudomonas aeruginosa, a significant nosocomial pathogen. Stepwise resistance was assessed by serial passage of colonies located nearest to the inhibition zone on antibiotic-containing gradient plates. The lowest frequencies of spontaneous resistance mutations were found with cefepime and imipenem; these drugs also resulted in the slowest appearance of resistance of spontaneous resistance mutations. In five wild-type P. aeruginosa strains, cefepime-selected isolates required a mean of 30 passages to reach resistance; resistance occurred more rapidly in strains selected with other cephalosporins. P. aeruginosa strains that produced β-lactamase or non-enzymatic resistance generally developed resistance more rapidly than wild-type strains. For most strains, resistance to all antibiotics except imipenem correlated with increased levels of β-lactamase activity. Cross-resistance of cephalosporin-selected resistant mutants to other cephalosporins was common. Cephalosporin-resistant strains retained susceptibility to imipenem and ciprofloxacin. Prom our in vitro study, we can conclude that the rate of development of resistance of P. aeruginosa is lower with cefepime compared with other cephalosporines.

Pneumocystis carinii pneumonia (PCP) is still an important complication and cause of death among patients with AIDS. It is known that bronchoalveolar lavage (BAL) can show that the pathogen is still present, even after effective treatment. The clinical relevance of this low degree of eradication is not clear, especially with regard to relapse and survival. Studies have shown that performing BAL at the end of treatment may be useful for identifying patients at increased risk of early relapse, but this value remains controversial, as does the prognostic value of the procedure. We performed a study in which BAL was repeated at the end of 3 weeks of treatment to detect the persistence of P. carinii, especially in cases of severe illness. Patients could receive a fourth week of treatment if the second BAL was positive. Our goal was to assess the value of a second BAL for HIV-infected patients with PCP in whom treatment had been effective.

A case of rhinocerebral mucormycosis occurring in a 41-year-old man with insulin-treated diabetes mellitus is reported. Microscopically, biopsy samples obtained from the left ethmoid and middle turbinate sinuses contained fungi that formed mycotic granulomas associated with multinucleate giant cell arteritis. The multinucleate giant cells contained broad, infrequently septate hyphase consistent with mucormycosis. The patient received surgical debridement with extenteration of the left orbit, and intravenous liposome-encapsulated amphotericin B. After 12 months, examination of the patient revealed complete healing. Multinucleate giant cell granulomas and arteritis are only exceptionally associated with rhinocerebral mucormycosis, but these histologic findings may be correlated with a progressive disease with better prognosis.

Liver biopsy (LB) has been advocated for the detection of mycobacterial infections in patients infected with human immunodeficiency virus (HIV). To determine the effect of the use of this procedure on survival, we compared it in terms of yield with histological findings and noninvasive microbiological procedures. We reviewed the cases of 98 patients who underwent 106 LBs as part of the diagnostic screening for fever of unknown origin. LB revealed 17 cases of mycobacterial infection. For all but one patient, the results of at least one noninvasive procedure were positive. In 85 cases where infections were not diagnosed by LB, 17 had infections documented by other procedures. When all culture results are considered, the mean (±SD) incubation time to the first positive culture was 15 ± 5 days, whereas the mean (±SD) incubation time to the first positive culture of an LB specimen was 28 ± 9 days. The survival time was not significantly increased for patients who underwent LB and had positive Ziehl-Neelsen-stained smears; these patients survived a mean (±SD) of 12 ± 11 months, whereas patients with negative smears survived a mean (±SD) of 9 ± 10 months. Noninvasive studies are preferable to LB for the diagnosis of mycobacterial infections in HIV-infected patients.