Murine T Cell Determination of Pregnancy Outcome: I. Effects of Strain, αβ T Cell Receptor, γδ T Cell Receptor,and γδ T Cell Subsets

PROBLEM: T cells bearing αβ T cell receptor (TcR) and γδ TcR are present at the fetomaternal interface, and the latter, which express surface activation markers, can react with fetal trophoblast cell antigens. What is the role of these cells? METHOD: Using stress-abortion-prone DBA/2-mated CBA/J and abortion-resistant C57/B16 mice, αβ, γδ, and CD8^+/- T cell subsets were measured in spleen and uterine decidua. The effect of immunization against abortion and administration of anti-TcR antibody in vivo was examined. Cytokine synthesis was measured by intracellular staining of Brefeldin A-treated cells. RESULTS: Abortion-prone matings showed an unexpected accumulation of γδ T cells beginning in the peri-implantation period and this was suppressed by immunization against abortion. The immunization deleted γδ T cells producing the abortogenic cytokines, TNF-α and γ-interferon, and increased production of the anti-abortive cytokines, IL-10 and transforming growth factor-β2 (TGF-β2). Immunization also boosted the number of αβ T cells which were present in the decidua as early as 2 days after implantation. In vivo injection of GL4 (anti-δ) depleted γδ T cells producing Th1 cytokines in the peri-implantation period, and prevented abortions, whereas H57 (anti-β) decreased the number of αβ T cells and led to 100% abortions. CD8⁺ T cells present in peri-implant decidua before onset of abortions were mostly αβ TcR⁺, although some were γδ⁺. Changes in γδ and αβ T cells in pregnancy were most dramatic in uterine tissue. CONCLUSION: Although decidual γδ T cells after formation of a distinct placenta and fetus produce anti-abortive TGF-β2-like molecules and IL-10, prior events can lead to abortion. High local production of TNF-α and γ-interferon develop during the peri-implantation phase because of an excessive increase in the Th1 cytokine⁺ subset of γδ cells; these cytokines may be contributed by other tissues in decidua, and the contribution of bioactive factors by γδ T cells may augment the cytokine pool. In contrast, αβ T cells (which may be inactivated by stress that causes abortions) may mediate the anti-abortive effect of alloimmunization. Alloimmunization involves a shift from a Th1 to a Th2 pattern in the γδ T cells in decidua.     

The role of γδ T cells in priming macrophages to produce tumor necrosis factor-α

The secretion of tumor necrosis factor (TNF)-α from macrophages is regulated by both priming and triggering signals. We found that macrophages from mice lacking γδ T cells [T cell receptor (TCR) δ^?/- mice], which lack the gene encoding the δ chain, produced only small amounts of TNF-α in response to lipopolysaccharide (LPS) and showed a reduced level of expression of CD14. Pre-incubation of macrophages from TCR δ-/- mice with γδ T cells from their TCR δ^+/- littermates restored their capacity to produce TNF-α in response to LPS. The priming activity of γδ T cells was in part inhibited by neutralizing anti-interferon (IFN)-γ monoclonal antibodies. Collectively, these results suggest that γδ T cells play a role in priming macrophages to a steady state of activation via IFN-γ secretion, which allows them to produce TNF-α when exposed to LPS.     

Interleukin-12 activates human γδ T cells: synergistic effect of tumor necrosis factor-α

γδ T cell populations are known to expand in response to intracellular bacterial infectious agents regardless of previous priming. We have shown previously that soluble factor(s) produced by Mycobacterium-stimulated monocytes activate cord blood γδ T cells to proliferate. In this study, we investigated whether cytokines produced by monocytes are responsible for γδ T cell activation in vitro: interleukin (IL)-1β, IL-6, IL-8, IL-12, tumor necrosis factor (TNF)-α and granulocyte/macrophage colony-stimulating factor were examined. Recombinant human IL-12 stimulated γδ T cells, but not αβ T cells in peripheral blood mononuclear cells, to express CD25 on their surfaces, and to expand in number in vitro. IL-12-primed γδ T cell numbers increased to a greater extent in the culture to which exogenous IL-2 (5 U/ml) was added. Anti-TNF-α monoclonal antibody inhibited IL-12-induced up-regulation of CD25 on γδ T cells, suggesting that endogenous TNF-α may play a role in IL-12-induced activation of γδ T cells. Recombinant TNF-α synergistically augmented IL-12-induced activation of γδ T cells. Furthermore, IL-12 up-regulated TNF receptors on γδ T cells in vitro: TNF-α binding to its receptor induced CD25 expression on the γδ T cells in an autocrine or paracrine fashion, or perhaps both. It also became evident that both IL-12 and TNF-α were produced by mycobacterial lysate-stimulated monocytes. Taken together, these results suggest that upon confrontation with mycobacterial organisms, γδ T cells can be quickly and antigen-nonspecifically activated by soluble factors including IL-12 and TNF-α, both of which are produced by mononuclear phagocytes in response to mycobacterial organisms.     

Expression of pro-inflammatory cytokines by TCRαβ+ T and TCRγδ+ T cells in an experimental model of colitis

An inflammatory bowel disease (IBD) comparable to human ulcerative colitis is induced upon transfer of T cell-depleted wild-type (F1) bone marrow into syngeneic T cell-deficient (tgε26) mice (F1 → tgε26). Previously we have shown that activated CD4⁺ T cells predominate in transplanted tgε26 mice, and adoptive transfer experiments verified the potential of these cells to cause disease in immunodeficient recipient mice. Using flow cytometry for the detection of intracellular cytokine expression, we demonstrate in the present study that large numbers of CD4⁺ and CD8⁺ TCRαβ⁺ T cells from the intraepithelial region and lamina propria of the colon of diseased, but not from disease-free mice, produced interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Large numbers of T cells from peripheral lymphoid tissues of these animals also expressed IFN-α and TNF-α, but few expressed interleukin-4, demonstrating g strong bias towards Th1-type T cell responses in these animals. TCRγδ⁺ T cells, typically minor constituents of the inflammatory infiltrate of the colon in F1 → tgε26 mice, also expressed IFN-γ at a high frequency upon CD3 stimulation. In light of these findings we examined the potential involvement of TCRγδ⁺ T cells by testing their ability to induce colitis in tgε26 mice. We report here that tgε26 mice transplanted with T cell-depleted bone marrow from TCRα^null and TCRβ^null animals developed IBD. Furthermore, disease in these mice correlated with the development of peripheral and colonic TCRαδ⁺ T cells capable of IFN-γ production. These results suggest that IFN-γ may be a common mediator of IBD utilized by pathogenic T cells of distinct phenotype.     

Preferentially expanding Vγ1+ γδ T cells are associated with protective immunity against Plasmodium infection in mice

γδ T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)‐CD40 signaling by γδ T cells induces protective immunity against the blood‐stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which γδ T‐cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vγ1⁺ cells, we saw that Vγ1⁺ γδ T cells were important for the control of PbXAT infection. Splenic Vγ1⁺ γδ T cells preferentially expand and express CD40L, and both Vγ1⁺ and Vγ4⁺ γδ T cells produce IFN‐γ during infection. Although expression of CD40L on Vγ1⁺ γδ T cells is maintained during infection, the IFN‐γ positivity of Vγ1⁺ γδ T cells is reduced in late‐phase infection due to γδ T‐cell dysfunction. In Plasmodium‐infected IFN‐γ signaling‐deficient mice, DC activation is reduced, resulting in the suppression of γδ T‐cell dysfunction and the dampening of γδ T‐cell expansion in the late phase of infection. Our data suggest that Vγ1⁺ γδ T cells represent a major subset responding to PbXAT infection and that the Vγ1⁺ γδ T‐cell response is dependent on IFN‐γ‐activated DCs.     

The homogeneity of the TCRδ repertoire expressed by the Thy-1dull γ δ T cell population is due to cellular selection

Thy-1^dull γ δ T cells are an unusual subset of mature TCRγ δ T cells characterized by their highly restricted TCR repertoire. In DBA/2 mice, they predominantly express the product of the Vγ1 gene together with that of a member of the Vδ6 subfamily (the Vδ6.4 gene) and their junctional sequences show very little diversity. To address the mechanisms underlying the expression of the restricted TCRγ δ repertoire, we have cloned all Vδ6 subfamily members present in DBA/2 mice and studied their frequency of expression in Thy-1^dull and Thy-1^bright γ δ thymocyte populations. Furthermore, we have also cloned non-functional Vδ6DδJδ1 rearrangements present in the Thy-1^dull γ δ T cell population and compared their Vδ6 gene utilization and their junctional sequences with those expressed by this population. Our results indicate that the restricted TCRδ repertoire expressed by the Thy-1^dull γ δ thymocytes results from cellular selection, rather than molecular constraints suggesting the existence of a limited set of self-ligands. Finally, phenotypic, functional and TCRγ δ repertoire analysis of Thy-1^dull γ δ T cells in β2 -microglobulin (β₂m)-deficient mice indicated that these putative ligands are not β₂m-dependent major histocompatibility complex class I or class I-like molecules.     

Soluble Receptors Neutralizing TNF-α and IL-1 Block Stress-Triggered Murine Abortion

PROBLEM: In several models of abortion in rodents, the success or failure of the implanted embryos is determined by a balance between pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-2, interleukin-1 (IL-1), and γ-interferon, and cytokines that counteract the former, such as interleukin-10 and transforming growth factor-β2 (TGF-β2)-related suppressor factor. Stress can trigger abortions in susceptible strains of mice and is thought to reflect the pathogenesis of some types of miscarriage in human pregnancy. In mice, stress increases levels of the abortogenic cytokine TNF-α and decreases the suppressive activity of TGF-β2-related factor via a neurotransmitter substance P (SP)-dependent pathway. Evidence for a role of pro-inflammatory cytokines in SP-mediated abortions in vivo is indirect. METHODS: Direct evidence for a role of IL-1 and TNF-α in stress-triggered abortions was sought by injecting pregnant female mice with soluble receptors neutralizing TNF-α (rhuTNFR: Fc) or IL-1 (rmIL-1R) beginning 1 day after implantation and prior to stress. RESULTS: The stress-triggered abortion rate was reduced by 68% when either TNF-α or IL-1 antagonists were injected. The stress-triggered decreased TGF-β2-like suppressive activity in the maternal uterine decidua was not restored by injection of either antagonist; indeed the soluble IL-1 receptor significantly reduced suppressive activity in unstressed control mice, and soluble TNF-α receptor had a lesser effect. CONCLUSIONS: Both IL-1 and TNF-α play a role in the pathogenesis of stress-triggered abortions, and may induce a compensatory physiological increase in suppressive activity in normal pregnancy counteracting pro-inflammatory cytokines.     

γδ T-Cell Subset Distribution in Human Semen From Fertile Donors

PROBLEM : γδ T-cell subset distribution has not been fully investigated in normal human semen. METHODS : We therefore carried out experiments by using a direct immunofluorescence staining technique followed by two-color cytofluorimetric analysis on mononuclear cell (MC) suspensions from ejaculates of ten healthy, fertile volunteers. Autologous peripheral blood MC were simultaneously analyzed and the results used for statistical comparison. RESULTS : The proportion of normal human semen lymphocytes bearing the γδ T-cell receptor for antigen was greatly increased compared with autologous circulating counterparts. Interestingly, the rise was mainly due to an overexpansion of cells expressing Vδl gene-encoded determinants on their surface. This contrasts with the normal blood picture, where most γδ T cells express Vδ2 conformational epitopes. CONCLUSIONS : The numerical and phenotypical differences in semen γδ T lymphocytes provide further evidence of a defined migrating lymphocyte subset balance in anatomically and physiologically distinct areas of the body. Their functional role, in terms of both helper and suppressor-cytotoxic activities in the nonsterile proximal portions of the male genital tract, now needs to be explored in detail.     

T cell receptor α gene rearrangement and transcription in adult thymic γδ cells

T cells belong to two separate lineages based on surface expression of αβ or γδ T cell receptors (TCR). Since during thymus development TCR β, γ, and δ genes rearrange before α genes, and γδ cells appear earlier than αβ cells, it has been assumed that αδ cells are devoid of TCR α rearrangements. We show here that this is not the case, since mature adult, but not fetal, thymic γδ cells undergo VJα rearrangements more frequently than immature αβ lineage thymic precursors. Sequence analysis shows VJα rearrangements in γδ cells to be mostly (70 %) nonproductive. Furthermore, VJα rearrangements in γδ cells are transcribed normally and, as shown by analysis of TCR β-/- mice, occur independently of productive VDJβ rearrangements. These data are interpreted in the context of a model in which precursors of αβ and γδ cells differ in their ability to express a functional pre-TCR complex.     

Decidua as a Site of Extrathymic VγI T-cell Differentiation

PROBLEM: Decidual tissue is an interface between the host and fetus, which is regarded as a natural allograft. We have reported the possible presence of extrathymic T cells in human decidua through the expression of recombinase-activating genes in the decidual CD16^? CD56^bright large granular lymphocytes. METHODS: In this study we analyzed expression of TCR Vγδ gene segments in peripheral lymphocytes and decidual and nonpregnant endometrial samples using RT-PCR and oligonucleotide hybridization. RESULTS: Interestingly, a limited repertoire of Vγ gene segments were discovered in decidual lymphocytes of normal pregnancy when compared with peripheral lymphocytes, whereas usage of Vδ gene segments were ubiquitous in peripheral and decidual lymphocytes. Strong expression of VγI gene segment, often exceeding 50% of total Vγ, were noted in all (13/13) pregnant decidual tissues obtained at different gestational stages. Interestingly, this predominance of VγI gene is also noted in nonpregnant endometrial samples and the decidua of patients with ectopic pregnancies. CONCLUSIONS: Our results suggest the nature of decidual VγI T cells as possible suppressors of rejective maternal cytotoxic T cells during the maintenance of normal pregnancies.     

反复自然流产患者母胎界面SOCS3蛋白、TNF-α及IL-10的表达

目的:研究反复自然流产患者蜕膜组织中细胞因子信号转导抑制因子SOCS3,细胞因子TNF-α及IL-10的表达,并与正常妊娠作对照。方法:Western blot检测SOCS3的表达,免疫组织化学法检测细胞因子TNF-α及IL-10的表达。结果:反复自然流产组蜕膜组织中SOCS3的表达明显降低(P<0.01),差异有统计学意义,IL-10表达降低(P<0.01),TNF-α表达增高(P<0.05),差异有统计学意义。结论:与正常妊娠相比,反复自然流产组蜕膜组织中SOCS3蛋白及IL-10表达降低,TNF-α表达增高,差异有统计学意义,说明反复自然流产患者母胎界面Th1/Th2失衡,SOCS3蛋白可能通过与细胞因子的相互调控作用影响Th1/Th2平衡导致流产发生。     

Tumor Necrosis Factor-α mRNA-Positive Cells in Spontaneous Resorption in Rodents

PROBLEM: It has been proposed that high rates of resorption/spontaneous abortion may result from interaction in the decidua of γ-interferon-producing natural killer (NK) cells and tumor necrosis factor (TNF)-α-producing macrophages. An increased release of TNF-α from placental tissue of resorptions has been reported, but macrophages producing TNF-α have so far not been demonstrated at the feto-maternal interface. Therefore, we have sought to identify TNF-α-producing cells by in situ hybridization at the feto-maternal interface in two inbred, well-characterized, and stable strains of laboratory rodents with high and low resorption rates. METHOD OF STUDY: Pregnant DBA/2-mated CBA/J mice with a resorption rate of 20% to 30% (dependent on NK cells and macrophages) and diabetes-resistant Bio-Breeding/ Edinburgh (DR-BB/E) rats with low resorption rates (presumed to result from chromosomal abnormalities) were studied. AsialoGMl⁺ cells were detected by immunohistochemistry, and TNF-α mRNA⁺ cells were detected by in situ hybridization. RESULTS: TNF-α mRNA⁺ cells were detected in DBA/2-mated CBA/J mice at the time of resorption but only at the trophoblast-decidual junction. AsialoGM1⁺ cells were present in decidua, as assessed by immunohistochemistry, but few if any gave a positive signal for TNF-α. In rat resorptions, TNF-α mRNA-positive cells were present within the yolk sac and in contact with the trophoblast, but not at the trophoblast-decidual junction. In neither species did a significant accumulation of detectable TNF-α mRNA⁺ cells occur before the usual time of onset of resorption. CONCLUSIONS: In the DBA/2-mated CBA/J mouse, the removal of the placenta is associated with removal of a thin rim of adherent decidua similar to the location of the TNF-α mRNA⁺ cells detected in this study. Our data suggest that increased TNF-α in tissues associated with failing feto-placental units may arise from infiltration/activation of scavenger cells from decidua that are likely to be macrophages. Local TNF-α production in decidua, which occurs as a prelude to resorption in the CBA x DBA/2 model, could not be detected due to the insensitivity of the TNF-α probe we used; the release of TNF-α from decidual tissue left after the removal of the placenta does not differ between resorbing and healthy implant sites. AsialoGM1⁺ cells did not seem to be major producers of TNF-α. TNF-α mRNA⁺ cells in a low rate of resorption (rat) model were only found on the fetal side of the trophoblast, and they may also represent a macrophage response (to dying embryo tissue) derived from a nondecidual source. The location of TNF-α mRNA⁺ cells may identify distinct and different mechanisms of resorption in rodents.     

Role of natural killer cells and TCRγ δ T cells in acute autoimmune encephalomyelitis

To elucidate the role of NK cells and TCRγ δ ⁺ T cells in acute experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats, the distribution, number and function of these cells were studied using several methods. Immunohistochemical and flow cytometric analysis revealed that a certain number of NK cells (17 % of the total inflammatory cells) infiltrated the central nervous system (CNS) at the peak stage of EAE and were mainly located in the perivascular region. On the other hand, virtually no TCRγ δ ⁺ T cells were found in the CNS. NK-T (NKR-P1⁺ TCRα β ⁺ ) cells were few and did not increase in number in the CNS and lymphoid organs. In the cytotoxic assay using YAC-1 cells, effector cells isolated from the spleen of rats at the peak of EAE showed essentially the same cytotoxicity as those isolated from normal controls although the total number of NK cells decreased to one fifth of that of normal rats. Furthermore, in vivo administration of anti-NK cell (3.2.3 and anti-asialo GM1), but not of anti-TCRγ δ (V65), antibodies exacerbated the clinical features of EAE and induced fatal EAE in some rats. These findings suggest that NK cells play a suppressive role in acute EAE whereas TCRγ δ ⁺ T cells are not involved in the development of or recovery from the disease.     

Stress Triggered Abortions Are Associated With Alterations of Granulated Cells in the Decidua

PROBLEM: Stress is known to be abortogenic in animals and humans. An increased decidual release of cytokines such as TNF-α and reduction in TGF-β2-related immunosuppressive activity has been proposed as the triggering mechanism. Substance P released by nerves in endometrium/decidua has been found to be the key neurotransmitter in this pathway. It is still unclear which cells are stimulated by substance P to produce the increased TNF-α level. METHOD: As a measure of local activation, the granulation of granulated metrial gland (GMG) cells was measured by flow cytometry after sonic plus immobilization stress of mice or substance P treatment of GMG cells (both isolated GMG cells and GMG-cell containing decidua). TNF-α release from decidua and isolated GMG cells was investigated using a TNF-α bioassay. The degranulation of uterine mast cell, another potential source of TNF-α, was examined in situ by Toluidine blue staining. RESULTS: We observed a striking increase in percentage of degranulated mast cells (8% r? 24%) in the uteri of stressed animals, whereas the granularity of GMG cells was decreased by stress but increased with treatment with substance P in vitro. Isolated GMG cells appeared to release in vitro cytotoxins active in the TNF-α bioassay, but the magnitude of this activity was not increased by stress or by substance P treatment. In contrast, disaggregated decidual tissue which is known to release increased amounts of TNF-α after stress, did increase activity in response to substance P in vitro. CONCLUSIONS: Uterine mast cells show activation as reflected by degranulation after stress exposure of pregnant mice and mast cells might be the cellular link between the neurotransmitter substance P and an increase in decidual TNF-α release that leads to abortion.     

Apoptosis of cultured mouse luteal cells induced by tumor necrosis factor-α and interferon-γ

Background: Macrophages and T lymphocytes have been identified in the regressing corpus luteum, and they are thought to participate in structural luteolysis (destruction and removal of luteal cells). Since these cells produce cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), we investigated the effects of these two cytokines on death of luteal cells in vitro. Methods: Mouse luteal cells were cultured in serum-free medium with TNF-α at 0,500,1,000,3,000, or 5,000 U/ml in the presence or absence of IFN-γ at 1,000 U/ml for 3 or 6 days. Then, for estimation of the actions of these cytokines on induction of luteal cell death, we determined the number of viable cells, the percentage of fragmented DNA in total DNA extracted from cultured cells, and the percentage of cells with fragmented DNA in their nuclei by the trypan blue exclusion test, the sensitive micromethod for DNA assay, and the in situ DNA 3′ end labeling method, respectively. DNA fragmentation was also analysed by agarose gel electrophoresis, and cultured cells were examined by electron microscopy. Results:On day 3 of culture, IFN-γ alone at 1,000 U/ml or TNF-α alone at 500–5,000 U/ml did not decrease the number of viable cells, but a combination of IFN-γ (1,000 U/ml) and TNF-α (5,000 U/ml) did. On day 6, IFN-γ alone at 1,000 U/ml or TNF-α alone at 500, 1,000 and 3,000 U/ml did not decrease the number of viable cells, whereas TNF-α alone at 5,000 U/ml did, and combinations of IFN-γ and TNF-α at 1,000, 3,000, and 5,000 U/ml decreased the number of viable cells in proportion to the concentration of TNF-α. On days 3–6 of culture, combinations of IFN-γ and TNF-α that decreased the number of viable cells also increased the percentages of fragmented DNA in total DNA of cultured luteal cells and the percentages of luteal cells with fragmented DNA in their nuclei. Agarose gel electrophoresis of fragmented DNA showed a ladder-like pattern, and electron microscopic examination showed luteal cells with the characteristics of apoptosis. Conclusions: The presence of IFN-γ modulates the ability of TNF-α to induce a reduction in the number of viable cells, although TNF-α alone at high concentrations can induce a reduction in the number of viable cells. © 1995 Wiley-Liss, Inc.     

Stress-Triggered Abortion: Inhibition of Protective Suppression and Promotion of Tumor Necrosis Factor-α (TNF-α) Release as a Mechanism Triggering Resorptions in Mice

PROBLEM: Stress adversely affects pregnancy outcome and has been implicated as an abortogen in both animals and humans. However, the mechanisms whereby stress aborts are largely unknown. Alloimmunization can prevent stress-triggered abortion, and immunization is known to increase transforming growth factor-β2 (TGF-(32)-related suppressive activity. METHOD: To investigate these mechanisms, DBA/2J males were mated to CBA/J or C3H/ HeJ females, and the pregnant females were exposed to ultrasonic sound stress for a period of 24 h between day 4.5 to 8.5 of pregnancy. RESULTS: Ultrasonic stress significantly elevated the resorption rate with a peak effect on day 5.5 in the CBA/J females and on day 4.5 in the LPS-resistant C3H/HeJ females. The tumor necrosis factor-α (TNF-α) release from the decidua was also elevated and the TGF-β2-mediated suppressive activity was significantly decreased. The resorption rate only increased when the TNF-α/TGF-β2 ratio was increased compared to the control. CONCLUSION: These data suggest that stress may inhibit protective suppressor mechanisms and promote secretion of abortogenic cytokines such as TNF-α. Possible mechanisms are discussed.     

The role of gamma/delta 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. METHOD OF STUDY: Review of literature and current data. RESULTS: In the decidua gamma/delta TCR positive cells significantly increase in number. A subset of gamma/delta T cells reacts with nonpolymorphic Class I or Class I like molecules. Trophoblast recognition is mediated by the V gamma 1 subset which recognize a conserved mammalian sequence on the trophoblast. Almost all gamma/delta T cells in the decidua are activated and use the V delta 1 chain, whereas the majority of human peripheral gamma/delta lymphocytes expresses V gamma 9/V delta 2 TCR. Peripheral gamma/delta T cells of healthy pregnant women preferentially use V gamma V delta 1 chains, on the other hand, those of recurrent aborters use the V gamma 9V delta 2 combination. Signaling via the V gamma 1.4V delta 1 receptor induces a Th2 type response, whereas activation of the lymphocytes via the V gamma 9V delta 2 receptor results in increased IL-12 production and natural killer (NK) activity. In the presence of progesterone, activated lymphocytes synthesize the progesterone induced blocking factor (PIBF), which inhibits NK activity and exerts an anti abortive effect in vivo. Decidual CD56+ and gamma delta+ cells are to a high extent the same population. CONCLUSION: All decidual CD56+ cells express PIBF, thus it cannot be excluded that local production of this substance contributes to low decidual NK activity and thus to the success of the pregnancy.     

γδ T cells come to stay: Innate skin memory in the Aldara model

The term immunological memory has long been a trademark restricted to adaptive lymphocytes such as memory B cells and plasma cells as well as memory CD8⁺ αβ T cells. In recent years, innate lymphocytes such as NK cells have also been shown to adapt to their environment by antigen‐specific expansion and selective survival. However, whether γδ T cells mount comparable memory responses to pathogenic stimuli is less well understood. In this issue of European Journal of Immunology, Hartwig et al. [Eur. J. Immunol. 2015. 45: 3022–3033] identify a subset of IL‐17‐producing γδ T cells that are capable of establishing long‐lived memory in the skin of mice exposed to imiquimod in the Aldara psoriasis model. These γδ T cells uniformly express a Vγ4⁺Vδ4⁺ TCR. They produce IL‐17A/F and persist in the dermis for long periods of time, also at untreated distal sites. Upon secondary challenge, experienced Vγ4⁺Vδ4⁺ cells show enhanced effector functions and mediate exacerbated secondary inflammation. These findings showcase innate γδ T‐cell memory that uses a single conserved public TCR combination. Furthermore, they provide mechanistic insight to the observed psoriatic relapses in patients in response to topical treatment with imiquimod.