Cristiana Gioia

Lack of CD27-CD45RA-V gamma 9V delta 2+ T cell effectors in immunocompromised hosts and during active pulmonary tuberculosis.

In humans, the circulating pool of mycobacteria-reactive Vγ9Vδ2+ T cells is expanded with age and may contribute to Mycobacterium tuberculosis immunosurveillance. We observed that two subsets of Vγ9Vδ2+ T cells could be identified on the basis of CD27 expression in immunocompetent adults, showing that functionally differentiated γδ T cells have lost CD27 expression. In contrast, the CD27−CD45RA−Vγ9Vδ2+ T cell subset of effector cells was absent in cord blood cells from healthy newborns and lacking in the peripheral blood from HIV-infected patients. Moreover, circulating Vγ9Vδ2+ T cell effectors were significantly reduced in patients with acute pulmonary tuberculosis, resulting in a reduced frequency of IFN-γ-producing cells after stimulation with nonpeptidic mycobacterial ligands. These observations indicate that monitoring and boosting γδ T cell effectors could be clinically relevant both in immunocompromised hosts and during active tuberculosis disease.

Cross-subtype Immunity against Avian Influenza in Persons Recently Vaccinated for Influenza

Seasonal influenza vaccination may induce heterosubtypic immunity against avian influenza virus (H5N1).

Association of Profoundly Impaired Immune Competence in H1N1v-Infected Patients with a Severe or Fatal Clinical Course

BACKGROUND Pandemic A/H1N1v influenza is characterized by a mild clinical course. However, a small subset of patients develops a rapidly progressive course caused by primary viral pneumonia or secondary bacterial infections that, in many cases, lead to death due to respiratory failure. The aim of the present study was to analyze the involvement of the immune response in the clinical presentation of H1N1v influenza. METHODS The differentiation and functional capability of T cells from H1N1v-infected patients presenting with either mild disease (n=22) or severe or fatal disease (n=6) were compared. Moreover, plasma cytokines and chemokines were quantified. RESULTS T cells from H1N1v-infected patients presenting with a severe clinical course resulted in impaired effector cell differentiation and failed to respond to mitogenic stimulation. T cell anergy was strictly associated with a severe acute phase of infection, but T cells could be restored in patients able to recover. Of interest, massive expression of CD95 marker was found on anergic T cells, suggesting an apoptosis-related mechanism. Finally, lower plasma levels of interferon-alpha and monocyte chemoattractant protein-1 were found in patients with a worse clinical course of influenza, suggesting impaired production of these cytokines. CONCLUSIONS Our results show a strict association between host immune competence and the severity of the clinical course of H1N1v infection. By monitoring host functional response, patients with an enhanced risk of developing influenza-associated severe complications could be identified in a timely manner.

IP-10 is an additional marker for tuberculosis (TB) detection in HIV-infected persons in a low-TB endemic country.

OBJECTIVE In Indian HIV-infected patients, IP-10 response to QuantiFERON-TB Gold In tube (QFT-IT) antigens has been associated to tuberculosis (TB). However, specificity for active TB was lower than that reported by QFT-IT, making accuracy for TB detection questionable. To investigate this uncertainty, likely due to India being highly endemic for TB, and to better identify TB correlates, we evaluated the IP-10-based assay in HIV-infected subjects in Italy, a low-TB endemic country. METHODS 195 individuals were prospectively enrolled; 118 were HIV-infected (21 with active TB, 97 without active TB, and distinguished as high/low-TB-risk). QFT-IT was performed and IP-10 was evaluated by ELISA. RESULTS Among the HIV-infected individuals, sensitivity for active TB was 66.7% by IP-10-based test and 52.4% (p = 1) by QFT-IT. IP-10-based assay showed a lower dependence on mitogen-response and CD4 counts than QFT-IT. Among subjects without active TB, a higher proportion of IP-10 responders was shown in high-TB-risk subjects than low-TB-risk subjects (40.0% vs 12.9%), similar to QFT-IT (37.1% vs 4.8%). Low-TB risk subjects showed 87.1% specificity for active TB by IP-10-based test vs 95.2% by QFT-IT. CONCLUSIONS In a low-TB endemic country, besides IFN-γ, IP-10 response to QFT-IT is associated with active TB and TB risk factors in HIV-infected patients with lower dependence on mitogen-response and CD4 counts.

Zoledronic acid and interleukin-2 treatment improves immunocompetence in HIV-infected persons by activating Vγ9Vδ2 T cells.

Objective:γδ T cells bearing the Vγ9Vδ2 T-cell receptor exert many antiviral effector functions in humans, including release of anti-HIV factors and direct cytotoxicity against virus-infected cells. Moreover, they are known to activate dendritic cells, improving antigen presentation function. After HIV infection, Vγ9Vδ2 T-cell number and reactivity are rapidly affected and they decrease upon disease progression. Bisphosphonate drugs such as zoledronic acid (Zol), used to treat bone diseases, have been shown to induce in vivo, in combination with interleukin-2, Vγ9Vδ2 T-cells’ activation. The aim of this work was to verify whether the administration of Zol in combination with interleukin-2 in HIV-infected patients might improve Vγ9Vδ2 T-cell function, including immune adjuvancy mediated by γδ-dendritic cell cross-talk. Design and methods:In HIV patients naive to antiretroviral therapy, we analyzed the effect of combined Zol and interleukin-2 treatment, in comparison to Zol alone, on Vγ9Vδ2 T-cell number, maturation and function, on dendritic cell activation and on HIV-specific CD8 T-cell response. Results:Zol and interleukin-2-combined treatment induced in-vivo Vγ9Vδ2 T-cell expansion and maturation. Paralleling Vγ9Vδ2 T-cell activation, increased dendritic cell maturation and HIV-specific CD8 T-cell responses were found. Conclusion:The specific modulation of Vγ9Vδ2 T-cell number and responsiveness after HIV infection may be at least transiently restored in vivo by Zol and interleukin-2 treatment. In this way, the immune effector mechanisms, secondary to Vγ9Vδ2 T-cell activation, were improved, suggesting a possible adjuvancy role of Zol and interleukin-2 treatment in restoring innate and specific competence in HIV-infected persons.

Activated Vγ9Vδ2 T cells trigger granulocyte functions via MCP-2 release

Vγ9Vδ2 T cells display a broad antimicrobial activity by directly killing infected cells and by inducing an effective adaptive immune response. The activation of Vγ9Vδ2 T cells by aminobisphosphonate drugs such as zoledronic acid (ZOL) results in a massive release of cytokines and chemokines that may induce a bystander activation of other immune cells. The aim of this work was to evaluate the ability of soluble factors released by ZOL-activated Vγ9Vδ2 T cells to induce granulocyte activation. We showed that soluble factors released by ZOL-stimulated Vγ9Vδ2 T cells activate granulocytes by inducing their chemotaxis, phagocytosis, and α-defensins release. Proteomic analysis allowed us to identify a number of cytokines and chemokines specifically released by activated Vγ9Vδ2 T cells. Moreover, MCP-2 depletion by neutralizing Ab revealed a critical role of this chemokine in induction of granulocyte α-defensins release. Altogether, these data show a Vγ9Vδ2-mediated activation of granulocytes through a bystander mechanism, and confirm the wide ability of Vγ9Vδ2 T-lymphocytes in orchestrating the immune response. In conclusion, an immune modulating strategy targeting Vγ9Vδ2 T cells may represent a key switch to induce an effective and well-coordinated immune response, and can be proposed as a way to strengthen the immune competence during infectious diseases.

Expansion of pre-terminally differentiated CD8 T cells in chronic HIV-positive patients presenting a rapid viral rebound during structured treatment interruption.

Objective: The influence of structured treatment interruption on effector/memory CD8 T cell dynamics was analysed in chronic HIV-infected patients showing a rapid or delayed viral rebound. Design: Structured treatment interruption consisted of at least one month of discontinuation, followed by highly active antiretroviral therapy (HAART) resumption. Two groups of HIV structured treatment interruption patients were selected on the basis of plasma viral HIV-RNA value (> 30 000 copies/ml, branched DNA): group A (n = 14), patients with a rapid viral rebound (within one month) and group B (n = 6), patients with a delayed or no viral rebound (after a minimum of 4 months). Methods: A clinical and immunological follow-up was performed at HAART suspension (t 0), one month from suspension (t 1), at HAART resumption (t 2), and 30 days from resumption (t 3). Results: A sustained viral rebound was observed in group A patients, showing a rapid expansion of circulating CD8 T lymphocytes. In this group, the frequencies of CD8 T cells releasing IFN-γ after mitogen-induced or Gag-specific stimulation were highly increased after HAART discontinuation. Nevertheless, these CD8 T lymphocytes were mainly composed of pre-terminally differentiated cytotoxic T lymphocytes (CTL) expressing a CCR7− CD27+/− CD45RA− phenotype and a reduced amount of perforin. In contrast, group B patients showed no significant changes in immunological parameters during a prolonged drug-free period. Conclusion: These data indicate that monitoring CD8 T cell dynamics during structured treatment interruption could be clinically relevant, and new therapeutic strategies should aim qualitatively to restore CTL effector functions.

Different cytokine production and effector/memory dynamics of alpha beta+ or gamma delta+ T-cell subsets in the peripheral blood of patients with active pulmonary tuberculosis.

Immunity to M.tuberculosis (MTB) infection consists of interactions between various T-cell subsets that control the infection and prevent further reactivation. We analysed the effector/memory T-cell dynamics and cytokines production in the peripheral blood of patients with pulmonary tuberculosis (TB). We observed that the frequency of CD4+ T-cell effectors was significantly increased during active TB, confirming a major role of this T-cell subset in TB immunity. Pre-terminally differentiated CD8+ T-lymphocytes were increased in the peripheral blood as well. In contrast, we observed a reduced number of effector mycobacteria-reactive γδ+ T-lymphocytes with a specific defects in reacting to mycobacterial nonpeptidic antigens, suggesting that this innate response is rapidly lost during TB infection. Nevertheless, the frequency of γδ+ T-cells effectors in TB patients was higher than the αβ+ T-cell response to peptide from MTB-ESAT-6 protein and quantitatively similar to PPD reactivity. Thus, αβ+and γδ+ T-cell differentiation and function are differently triggered by active TB infection.

Anti–Severe Acute Respiratory Syndrome Coronavirus Immune Responses: The Role Played by Vγ9Vδ2 T Cells

Abstract Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus (SARS-CoV) strain. Analyses of T cell repertoires in health care workers who survived SARS-CoV infection during the 2003 outbreak revealed that their effector memory Vγ9Vδ2 T cell populations were selectively expanded ∼3 months after the onset of disease. No such expansion of their αβ T cell pools was detected. The expansion of the Vγ9Vδ2 T cell population was associated with higher anti–SARS-CoV immunoglobulin G titers. In addition, in vitro experiments demonstrated that stimulated Vγ9Vδ2 T cells display an interferon-γ–dependent anti–SARS-CoV activity and are able to directly kill SARS-CoV–infected target cells. These findings are compatible with the possibility that Vγ9Vδ2 T cells play a protective role during SARS

Levels of Interleukin-15 in Plasma May Predict a Favorable Outcome of Structured Treatment Interruption in Patients with Chronic Human Immunodeficiency Virus Infection

Structured treatment interruption (STI) may help to alleviate the problems associated with long-term antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients. We analyzed the role that baseline levels of cytokines in plasma play as markers of a favorable outcome of STI. Two groups of patients were defined: STI responders and STI nonresponders. STI responders showed a higher baseline concentration of interleukin (IL)-15 in plasma than did STI nonresponders and showed lower levels of tumor necrosis factor (TNF)-alpha during STI. No differences were observed in levels of IL-2, IL-7, or interferon-alpha in plasma. Our data show that (1) levels of TNF-alpha in plasma correlate with HIV viremia and (2) monitoring baseline levels of IL-15 in plasma allows for the identification of a favorable outcome of STI.