Laszlo Szereday

Progesterone as an immunomodulatory molecule

Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens gamma/delta TCR+ cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking factor (PIBF). PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect.

The Immunological Pregnancy Protective Effect of Progesterone Is Manifested via Controlling Cytokine Production

PROBLEM: This study was aimed at investigating the involvement of an altered cytokine pattern in the immunomodulatory and anti‐abortive effects of a progesterone‐induced immunomodulatory protein (PIBF).

Cytokine production by lymphocytes in pregnancy.

PROBLEM: In the presence of progesterone lymphocytes of pregnant women release a 34‐ kDa protein named the progesterone‐induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti‐abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF‐ and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated.

Decrease in CD3-negative-CD8dim+ and Vδ2/Vγ9 TcR + peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection

BACKGROUND/AIMS As chronic hepatitis C virus (HCV) infection is associated with impaired natural killer (NK) cell cytotoxicity, we examined the phenotypes and perforin expression of peripheral blood lymphocytes, as well as the effect of interferon-alpha2b (IFN-alpha2b) therapy. METHODS Thirty-three patients had chronic hepatitis C, and of them 12 had been on IFN-alpha2b treatment. Eleven individuals had been treated earlier with IFN-alpha2b and completely cured, and eight were HCV carriers with persistently normal serum alanine aminotransferase. Three-colour flow cytometry was used to measure the percentage of CD3(+/-)CD8+, CD3+CD4+, gammadeltaTcR+, Vdelta2 TcR+, Vgamma9 TcR+, Vdelta1 TcR+, CD3-CD16+, CD3-CD56+, CD19+ and perforin-positive cells. NK cell activity was assessed by single cell cytotoxic and flow cytometric assay. RESULTS Patients with chronic hepatitis C showed an impaired NK cytotoxicity, decreased percentage of CD3-negative-CD8dim-positive (NK subtype) and Vgamma9/Vdelta2 TcR+ as well as perforin-positive T lymphocytes, compared to controls and to those who were cured from HCV infection. IFN-alpha2b increased NK cell cytotoxicity and the percentage of perforin-positive lymphocytes. CONCLUSIONS Our findings suggest that in chronic HCV infection a decreased percentage of CD3(-)CD8+, Vgamma9/Vdelta2 TcR+ and perforin-positive T cells and simultaneous decreased peripheral NK activity may contribute to the impaired cellular immune response and the chronicity of the disease.

The role of γ/δ T cells in progesterone-mediated immunomodulation during pregnancy: A review

PROBLEM: To determine if pregnancy is recognized by the immune system and if inadequate recognition of fetal antigens might result in failed pregnancy.

Progesterone and Non‐specific Immunologic Mechanisms in Pregnancy

PROBLEM: Progesterone‐dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone‐induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti‐abortive effect in mice. Recently we have shown that PIBF induces a Th2 shift in vitro. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss.

Invariant Vα7.2-Jα33 TCR is expressed in human kidney and brain tumors indicating infiltration by mucosal-associated invariant T (MAIT) cells

The anti-tumor response of human invariant NKT (NKT) cells is well established. A novel T cell subset, mucosal-associated invariant T (MAIT) cells, possesses similar regulatory properties to NKT cells in autoimmune models and disease. Here, we examined the clonality of four T cell subsets expressing invariant alphaTCR, including Valpha7.2-Jalpha33 of MAIT cells, in 19 kidney and brain tumors. The MAIT clonotype was identified and co-expressed with NKT clonotype in half of the tumors. In contrast, two other invariant T cell clonotypes (Valpha4 and Valpha19) were not present in tumors. Such tumors also expressed Vbeta2 and Vbeta13, the restricted TCRbeta chain of MAIT cells and the antigen-presenting molecule MR1. A high percentage of infiltrating T cells was CD8+ and expressed HLA-DR suggesting activation. Although the MAIT alphaTCR was identified in both peripheral CD56+ and CD56- subsets, infiltrating lymphocytes were CD56 negative. The clonal presence of MAIT cells in tumors correlated with the expression of pro-inflammatory cytokines but no IL-4, IL-5 and IL-10, suggesting that a pro-inflammatory subset of human MAIT cells may exist. Our data imply that a CD56- subset of MAIT cells may participate in tumor immune responses similarly to NKT cells.

Recognition of Nonclassical HLA Class I Antigens by γδ T Cells During Pregnancy

The healthy trophoblast does not express classical HLA-A and HLA-B products; therefore, an MHC-restricted recognition of trophoblast-presented Ags is unlikely. In the decidua and also in peripheral blood of healthy pregnant women, γδ T cells significantly increase in number. We investigated the possible role of γδ T cells in recognition of trophoblast-presented Ags. PBL and isolated γδ T cells from healthy pregnant women as well as from those at risk for premature pregnancy termination were conjugated to choriocarcinoma cells (JAR) transfected with nonclassical HLA Ags (HLA-E, HLA-G). To investigate the involvement of killer-inhibitory/killer-activatory receptors in trophoblast recognition, we tested the effect of CD94 block on cytotoxic activity of Vδ2+ enriched γδ T cells to HLA-E- and/or HLA-G-transfected targets. Lymphocytes from healthy pregnant women preferentially recognized HLA− choriocarcinoma cells, whereas those from pathologically pregnant patients did not discriminate between HLA+ and HLA− cells. Normal pregnancy Vδ2+ T cells conjugated at a significantly increased rate to HLA-E transfectants, whereas Vδ2+ lymphocytes from pathologically pregnant women did not show a difference between those and HLA− cells. Blocking of the CD94 molecule of Vδ2+ lymphocytes from healthy pregnant women resulted in an increased cytotoxic activity to HLA-E-transfected target cells. These data indicate that Vδ2+ lymphocytes of healthy pregnant women recognize HLA-E on the trophoblast, whereas Vδ1 cells react with other than HLA Ags. In contrast to Vδ2+ lymphocytes from healthy pregnant women, those from women with pathological pregnancies do not recognize HLA-E via their killer-inhibitory receptors and this might account for their high cytotoxic activity.

Immunoactivation in preeclampsia: Vδ2+ and regulatory T cells during the inflammatory stage of disease

Recent data suggest a dominant role of the innate, rather than the adaptive immune system in pregnancy-related immunoregulation. gamma/delta T cells, that comprise a minor subpopulation of human peripheral blood lymphocytes, represent a link between the innate and the acquired immune systems. However little is known about how they function in preeclampsia, which is suggested to be associated with a Th1 predominant immune response. The aim of our study was to investigate the presence and phenotype of Vdelta2+ cells and of regulatory T cells in the pathogenesis of preeclampsia. Since Vdelta2+ T cell function has been shown to be altered in patients with preeclampsia we investigated the expression of perforin, Fas and TIM-3 by Vdelta2+ T cells and the possible role of activating and inhibitory NK cell receptors as well as of regulatory T cells. Vdelta2+ T cells of preeclamptic patients demonstrated an increased perforin and IFNgamma production, which could be explained by dysregulation of NK cell receptor expression. These Th1 polarized cells were less susceptible to apoptosis than Vdelta2+ T cells from healthy pregnant women. Our data suggest that activated Vdelta2+ T cells of preeclamptic women have an increased cytotoxic potential, which may be due to altered expression of NK cell inhibitory and activating receptors. In this study we report a series of observations, which taken together suggest the role of multiple pathways in generating an exaggerated systemic inflammatory response observed in the clinical stage of preeclampsia.

γ/δ T cell subsets in patients with active Mycobacterium tuberculosis infection and tuberculin anergy

Earlier data suggest that γ/δ T cells may play an important role in the immune response to Mycobacterium tuberculosis. The aim of this study was to determine the percentage of different γ/δ subsets in peripheral blood of active tuberculosis patients with a positive or negative tuberculin reaction. Thirty‐eight patients infected with M. tuberculosis and 22 healthy controls were included in the study. Venous blood was taken before starting antimycobacterial treatment. Lymphocytes were reacted with monoclonal antibodies specific for different γ/δ V chains (Vδ1, Vδ2, Vγ9 and Vγ4). The results were analysed in the context of tuberculin reactivity and X‐ray findings. Our results revealed a selective loss of Vγ9/Vδ2 T cells in the peripheral blood of tuberculin‐negative patients with active tuberculosis compared to healthy controls, while the ratio of Vγ9/Vδ2 T cells in the peripheral blood of patients with a positive skin test did not differ from that of healthy controls. These findings demonstrate a relationship between the loss of the major M. tuberculosis‐reactive subset of γδ T cells and the absence of tuberculin reactivity. The data are consistent with the hypothesis that γδ T cells play a role in the protective immune response to M. tuberculosis infection.