Phenotypic characterization of regulatory T cells from antiretroviral‐naive HIV‐1‐infected people

Regulatory T (Treg) cells play a key role in dampening excessive immune activation. However, antiretroviral therapy (ART) ‐naive HIV‐1 infection maintains the immune system in a sustained state of activation that could alter both Treg cell surface markers and functions. As Treg cell surface markers are directly linked to their functions the overall objective of this study was to determine how ART‐naive HIV infection affects the phenotypic properties of Treg cells. Our data showed that in ART‐naive HIV‐1 infection, Treg cells are dominated by effector (CD45RA⁺ CD27⁻ CCR7⁻ CD62L⁻) and effector memory (CD45RA⁻ CD27⁻ CCR7⁻ CD62L⁻) cells. In contrast Treg cells from HIV‐negative individuals were mainly naive (CD45RA⁺ CD27⁺ CCR7⁺ CD62L⁺) and central memory (CD45RA⁻ CD27⁺ CCR7⁺ CD62L⁺) cells. Whereas effector and effector memory Treg cells showed enhanced expression of CD39 (P < 0·05), CD73 (P < 0·001), HLA‐DR and CD38 (P < 0·001); naive and central memory Treg cells showed a significant reduction in the expression of these markers. Overall Treg cell frequencies within total CD4⁺ T cells correlated positively with plasmatic HIV‐1 viral load. As increased viral load is associated with augmented CD4⁺ T‐cell destruction; this could suggest a resistance of peripheral Treg cells to HIV‐1 destruction. Hence the modulation of Treg cell phenotype and frequencies could be considered in designing immunotherapeutic strategies targeting immune system restoration during HIV‐1 infection.     

Association between discordant immunological response to highly active anti‐retroviral therapy,regulatory T cell percentage,immune cell activation and very low‐level viraemia in HIV‐infected patients

The mechanisms sustaining the absence of complete immune recovery in HIV‐infected patients upon long‐term effective highly active anti‐retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T_regs) or very low‐level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross‐sectional study in HIV‐infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4⁺ T cell count (> or < 500/mm³). Clinical and virological data (including very low‐level viraemia) were collected. In parallel, immunophenotyping of CD4⁺ lymphocytes, including T_reg subsets, and CD8⁺ T cells was performed. Percentages of activated CD4⁺ T cells, T_regs, effector T_regs and terminal effector T_regs were found to be significantly elevated in iIR. Neither the percentage of activated CD8⁺ T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4⁺ T cell count and percentage of T_regs were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long‐term HAART, activation of CD4⁺ and CD8⁺ T cells, T_reg percentages and very low‐level viraemia. Causative interactions between T_regs and CD4⁺ T cells should now be explored prospectively in a large patients cohort.     

New cohorts of naive T cells exacerbate ongoing allergy but can be suppressed by regulatory T cells

Although as pretreatment oral tolerance is a potent means to achieve systemic suppression, its application in ongoing disease is controversial. Here we propose that availability of naive T cells may critically determine whether immunological tolerance is achieved during ongoing antigenic reactivity. Infusion of naive antigen-specific T cells into mice directly prior to eliciting a secondary Th2 response induces these naive cells to actively engage in the antigenic response despite presence of established memory. Naive antigen-specific T-cells divided faster, produced more interleukin (IL)-2, IL-4 and IL-5 and enhanced immunoglobulin E (IgE) release during a secondary Th2 response, compared with naive T cells that were infused prior to a primary response. Despite such contribution by new cohorts of naive T cells co-infusion of mucosal Tr together with naive T cells could suppress enhanced IgE release during a secondary Th2 response. We conclude that naive T cells contribute to a secondary Th2 response and although they can still be suppressed in the presence of sufficient numbers of mucosal Tr, they may interfere with potential therapeutic application of mucosal tolerance.     

Human leucocyte antigen‐Bw4 and Gag‐specific T cell responses are associated with slow disease progression in HIV‐1B‐infected anti‐retroviral therapy‐naive Chinese

In China, the majority of human immunodeficiency virus (HIV) infections are predominately subtype B. It is important to characterize the HIV‐1 subtype B‐specific and its T cell response within the Chinese population, with the aim of identifying protective correlates of immunity to control HIV‐1 infections. In this study, we performed a comprehensive analysis looking into the magnitude/strength of T cell responses directed at the Gag protein of the HIV‐1 subtype B, one of the most conserved HIV‐1 proteins. The study group consisted of anti‐retroviral native and chronic HIV‐1 subtype B‐infected individuals. We used enzyme‐linked immunospot (ELISPOT) assay to quantify the total T cell responses to HIV‐1 Gag at the single peptide level. Twenty‐eight (38%) peptides were recognized in 24 (82·8%) individuals. The p24 was identified as the most frequently recognized subunit protein with the greatest T cell response in the test, which correlated positively with CD4⁺ T cell count and inversely with viral load (VL). At the level of the human leucocyte antigen (HLA) supertypes, we detected the highest levels and a significant correlation with both the CD4⁺ T cell count and the VL with Gag T cell responses in Bw4/Bw4. These findings demonstrate that (i) the HIV‐1B Gag p24‐specific immune responses play an important role in controlling viral replication and slowing clinical progression; and (ii) HLA‐Bw4/Bw4 allele has stronger T cell responses, which is associated with slow clinical progression in Chinese HIV patients.     

T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV‐infected children on anti‐retroviral therapy in Nairobi,Kenya

HIV‐infected children are less capable of mounting and maintaining protective humoral responses to vaccination against measles compared to HIV‐uninfected children. This poses a public health challenge in countries with high HIV burdens. Administration of anti‐retroviral therapy (ART) and revaccinating children against measles is one approach to increase measles immunity in HIV‐infected children, yet it is not effective in all cases. Immune anergy and activation during HIV infection are factors that could influence responses to measles revaccination. We utilized a flow cytometry‐based approach to examine whether T cell anergy and activation were associated with the maintenance of measles‐specific immunoglobulin (Ig)G antibodies generated in response to measles revaccination in a cohort of HIV‐infected children on ART in Nairobi, Kenya. Children who sustained measles‐specific IgG for at least 1 year after revaccination displayed significantly lower programmed cell death 1 (PD‐1) surface expression on CD8⁺ T cells on a per‐cell basis and exhibited less activated CD4⁺ T cells compared to those unable to maintain detectable measles‐specific antibodies. Children in both groups were similar in age and sex, CD4⁺ T cell frequency, duration of ART treatment and HIV viral load at enrolment. These data suggest that aberrant T cell anergy and activation are associated with the impaired ability to sustain an antibody response to measles revaccination in HIV‐infected children on ART.     

Depletion of CD4+CD25+ regulatory T cells enhances natural killer T cell‐mediated anti‐tumour immunity in a murine mammary breast cancer model

Both invariant natural killer T (NK T) cells and CD4⁺CD25⁺ T regulatory cells (T_regs) regulate the immune system to maintain homeostasis. In a tumour setting, NK T cells activated by α‐galactosylceramide (α‐GalCer) execute anti‐tumour activity by secreting cytokines. By contrast, T_regs intrinsically suppress antigen‐specific immune responses and are often found to be elevated in tumour patients. In this study, we have shown that T_regs regulate NK T cell function negatively in vitro, suggesting a direct interaction between these cell types. In a murine mammary tumour model, we demonstrated that administration of either α‐GalCer or anti‐CD25 antibody alone markedly suppressed tumour formation and pulmonary metastasis, and resulted in an increase in the survival rate up to 44% (from a baseline of 0%). When treatments were combined, depletion of T_regs boosted the anti‐tumour effect of α‐GalCer, and the survival rate jumped to 85%. Our results imply a potential application of combining T_reg cell depletion with α‐GalCer to stimulate NK T cells for cancer therapy.     

N‐Ethyl‐N‐nitrosourea mutagenesis in the mouse provides strong genetic and in vivo evidence for the role of the Caspase Recruitment Domain (CARD) of CARD‐MAGUK1 in T regulatory cell development

Natural regulatory T (nTreg) cells generated in the thymus are essential throughout life for the maintenance of T‐cell homeostasis and the prevention of autoimmunity. T‐cell receptor (TCR)/CD28‐mediated activation of nuclear factor‐κB and (J)un (N)‐terminal kinase pathways is known to play a key role in nTreg cell development but many of the predicted molecular interactions are based on extrapolations from non‐Treg cell TCR stimulation with non‐physiological ligands. For the first time, we provide strong genetic evidence of a scaffold function for the Caspase Recruitment Domain (CARD) of the TCR signalling protein CARD‐MAGUK1 (CARMA1) in nTreg cell development in vivo. We report two, new, N‐ethyl‐N‐nitrosourea‐derived mutant mice, Vulpo and Zerda, with a profound block in the development of nTreg cells in the thymus as well as impaired inducible Treg cell differentiation in the periphery. Despite independent heritage, both mutants harbour different point mutations in the CARD of the CARMA1 protein. Mutations in vulpo and zerda do not affect expression levels of CARMA1 but still impair signalling through the TCR due to defective downstream Bcl‐10 recruitment by the mutated CARD of CARMA1. Phenotypic differences observed between Vulpo and Zerda mutants suggest a role for the CARD of CARMA1 independent of Bcl‐10 activation of downstream pathways. We conclude that our forward genetic approach demonstrates a critical role for the CARD function of CARMA1 in Treg cell development in vivo.     

Indirect presentation in the thymus limits naive and regulatory T‐cell differentiation by promoting deletion of self‐reactive thymocytes

Acquisition of T‐cell central tolerance involves distinct pathways of self‐antigen presentation to thymocytes. One pathway termed indirect presentation requires a self‐antigen transfer step from thymic epithelial cells (TECs) to bone marrow‐derived cells before the self‐antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context‐dependent, potentially due to variation in self‐antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane‐bound transgenic self‐antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow‐derived antigen‐presenting cells, insHEL‐mediated thymocyte deletion was abolished, whereas thyroHEL‐mediated deletion occurred at a later stage of thymocyte development and Foxp3⁺ regulatory T‐cell differentiation increased. Indirect presentation increased the strength of T‐cell receptor signalling that both self‐antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self‐reactive thymocytes.     

Interleukin-15 production by monocyte-derived dendritic cells and T cell proliferation in HIV-infected patients with discordant response to highly active antiretroviral therapy

A discordant response to highly active antiretroviral therapy (HAART) occurs when CD4 T cell counts are stable or increased over time despite persistently detectable HIV-RNA levels. In order to identify immunological factors affecting discordant treatment responses, a total of 27 HIV-infected patients were studied: (a) 10 naive patients (mean CD4+ = 101.5 cells/microl; mean HIV-RNA = 4.8 log10 copies/ml); (b) seven responder patients (mean CD4+ = 908.9 cells/microl); and (c) 10 discordant patients (mean CD4+ = 396.1 cells/microl; mean HIV-RNA = 5.4 log10 copies/ml). Five healthy blood donors were included as HIV-seronegative controls. The following parameters were evaluated: interleukin (IL)-15 production by monocyte-derived dendritic cells (MDDC) after stimulation with lypopolysaccaride (LPS) and Candida albicans; recall and HIV-1-specific antigen lymphocyte proliferation (LP). Increased levels of IL-15 production by MDDC after stimulation with LPS and C. albicans were found both in discordant patients and responder patients. Conversely, a strong reduction of IL-15 levels was observed in naive patients. Discordant patients developed positive LP responses to C. albicans and HIV-1 p24. LP in response to C. albicans and HIV-1 p24 was also positive in responder patients. Decreased LP response was found in naive patients. In conclusion, HIV-infected patients with discordant viro-immunological responses to HAART present increased levels of IL-15 production by MDDC and enhanced recall and HIV-1-specific antigen LP responses, suggesting an improvement in indices of immune function.     

Strong and sustained effector function of memory‐ versus naïve‐derived T cells upon T‐cell receptor RNA transfer: Implications for cellular therapy

Current protocols used to select CMV‐specific T cells for adoptive immunotherapy focus on virus‐specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem‐cell transplantation (HSCT) from CMV‐seronegative donors. Here, we redirected T cells of CMV‐seronegative donors with a human genetically engineered TCR recognizing an HLA‐A*0201‐binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non‐viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve‐derived T‐cell subsets were both efficiently transfected by TCR‐RNA, memory‐derived T cells showed much stronger levels of HLA‐A*0201‐restricted cytolytic activity to CMV‐infected fibroblasts and maintained acquired function for 5–10 days. In addition to redirection of CD8⁺ cytotoxic T cells, TCR‐RNA transfection was capable of redirecting CD4⁺ T cells into potent Ag‐specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve‐derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus‐specific CD4⁺ and CD8⁺ T‐cell function. CMV TCR‐RNA may represent a suitable therapeutic ‘off‐the‐shelf’ reagent to be used in severe CMV infections of HSCT patients when endogenous CMV‐specific T‐cell immunity is insufficient.     

Partial and transient modulation of the CD3–T‐cell receptor complex,elicited by low‐dose regimens of monoclonal anti‐CD3, is sufficient to induce disease remission in non‐obese diabetic mice

It has been established that a total of 250 μg of monoclonal anti‐mouse CD3 F(ab′)₂ fragments, administered daily (50 μg per dose), induces remission of diabetes in the non‐obese diabetic (NOD) mouse model of autoimmune diabetes by preventing β cells from undergoing further autoimmune attack. We evaluated lower‐dose regimens of monoclonal anti‐CD3 F(ab′)₂ in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3–T‐cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4⁺, CD8⁺ and CD4⁺ FoxP3⁺ T cells. Four doses of 2 μg (total dose 8 μg) induced 53% remission of diabetes, similarly to the 250 μg dose regimen, whereas four doses of 1 μg induced only 16% remission. While the 250 μg dose regimen produced nearly complete and sustained modulation of the CD3 –TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4⁺ and CD8⁺ T cells decreased, whereas the proportions of CD4⁺ FoxP3⁺ T cells increased; these effects were transient. Mice with greater residual β‐cell function, estimated using blood glucose and C‐peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti‐CD3 that produced only partial and transient modulation of the CD3–TCR complex induced remission rates comparable to higher doses of monoclonal anti‐CD3. Accordingly, in a clinical setting, lower‐dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti‐CD3, potentially including reductions in cytokine release‐related syndromes and maintenance of pathogen‐specific immunosurveillance during treatment.     

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3⁺ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.     

Macrophage‐mediated psoriasis can be suppressed by regulatory T lymphocytes

We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops psoriasis‐like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro‐inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis‐like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF‐mediated psoriasis, ihTNFtg mice were crossbred into RAG1^KO mice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1^KO or wild‐type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild‐type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3‐positive cells into RAG1^KO or wild‐type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro‐inflammatory activity of macrophages, which are the major immune effector cells in hTNF‐mediated psoriasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Increased CTLA‐4+ T cells may contribute to impaired T helper type 1 immune responses in patients with chronic obstructive pulmonary disease

Impaired T helper type 1 (Th1) function is implicated in the susceptibility of patients with chronic obstructive pulmonary disease (COPD) to respiratory infections, which are common causes of acute exacerbations of COPD (AECOPD). To understand the underlying mechanisms, we assessed regulatory T (Treg) cells and the expression of an inhibitory T‐cell receptor, cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4). Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with AECOPD (n = 17), patients with stable COPD (sCOPD; n = 24) and age‐matched healthy non‐smoking controls (n = 26) were cultured for 24 hr with brefeldin‐A or monensin to detect intracellular or surface CTLA‐4 (respectively) by flow cytometry. T cells in PBMC from AECOPD (n = 9), sCOPD (n = 14) and controls (n = 12) were stimulated with anti‐CD3 with and without anti‐CTLA‐4 blocking antibodies and cytokines were quantified by ELISA. Frequencies of circulating T cells expressing intracellular CTLA‐4 were higher in sCOPD (P = 0·01), whereas patients with AECOPD had more T cells expressing surface CTLA‐4 than healthy controls (P = 0·03). Increased frequencies of surface CTLA‐4⁺ CD4⁺ T cells and CTLA‐4⁺ Treg cells paralleled increases in plasma soluble tumour necrosis factor receptor‐1 levels (r = 0·32, P = 0·01 and r = 0·29, P = 0·02, respectively) in all subjects. Interferon‐γ responses to anti‐CD3 stimulation were inversely proportional to frequencies of CD4⁺ T cells expressing intracellular CTLA‐4 (r = −0·43, P = 0·01). Moreover, CTLA‐4 blockade increased the induction of interferon‐γ, tumour necrosis factor‐α and interleukin‐6 in PBMC stimulated with anti‐CD3. Overall, chronic inflammation may expand sub‐populations of T cells expressing CTLA‐4 in COPD patients and therefore impair T‐cell function. CTLA‐4 blockade may restore Th1 function in patients with COPD and so aid the clearance of bacterial pathogens responsible for AECOPD.     

DRB1*0402 may influence arthritis by promoting naive CD4+ T‐cell differentiation in to regulatory T cells

HLA‐DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen‐induced arthritis (CIA), while HLA‐DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4⁺ T‐cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen‐specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4⁺ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN‐γ. *0401 Tg mice harbor memory CD4⁺ T cells that differentiate into IL‐17⁺ cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg‐cell numbers in *0401 Tg mice, causes immune dysregulation.     

Abatacept (cytotoxic T lymphocyte antigen 4‐immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non‐responding to anti‐tumour necrosis factor‐α agents

The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti‐tumour necrosis factor (TNF)‐α have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (T_reg) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non‐responders to one TNF‐α blocking agent, who received abatacept + MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While T_reg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and T_reg cell function is impaired in RA patients not responding to the first anti‐TNF‐α agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti‐TNF‐α failed, are immunologically prone to benefit from an agent targeting a different pathway.     

Programmed death (PD)‐1 molecule and its ligand PD‐L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus‐1‐infected individuals

Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1⁺ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4⁺ and CD8⁺ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1⁺ patients. Naive (CCR7⁺CD45RA⁺) CD8⁺ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7^‐CD45RA^–(T_EM)] were increased in HIV‐1⁺ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7⁺CD45RA^– (T_CM); P = 0·0116], T_EM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1⁺versus controls. PD‐L1 was increased in CD4 T_EMRA (CCR7^‐CD45RA⁺, P = 0·0119), CD8 T_EM (P = 0·0494) and CD8 T_EMRA (P = 0·0282) of aviraemic HIV‐1⁺versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1.     

Reduced maternal regulatory T cell numbers and increased T helper type 2 cytokine production are associated with elevated levels of immunoglobulin E in cord blood

Background There is evidence that the basis of an atopic‐skewed immune response is acquired early in life, perhaps at the fetal stage. Thus, we hypothesized that the development of the fetal immune system might be influenced by maternal regulatory T cells (Treg) and maternal T cell cytokine production during pregnancy. The aim of the present study was to assess the influence of maternal Treg and cytokine production during pregnancy on Treg and atopy at birth. Methods Within the mother–child study LINA (Lifestyle and Environmental factors and their Influence on Newborns Allergy risk), we determined the frequency and function of Treg and the total IgE concentration in pregnant women in the 34th week of gestation and in corresponding cord bloods at birth (n=24). Furthermore, we assessed how maternal mitogen‐induced T‐helper type 1/T‐helper type 2 and inflammatory cytokines influence the level of cord blood Treg and IgE. Results Frequencies of CD4⁺CD25^high T cells were higher (P=0.001), whereas percentages of FOXP3⁺ T cells were lower (P<0.001) in cord blood cells compared with maternal blood. Reduced maternal CD4⁺CD25^high Treg frequencies correlated with increased total IgE concentrations at the 34th week of gestation (r=?0.32, P=0.028) and with increased IgE concentrations in cord blood (r=?0.50, P<0.001). Elevated maternal mitogen‐induced Th2 cytokine production was related to increased total IgE levels in the serum of corresponding cord bloods (IL‐4, r=0.53; IL‐5, r=0.43; IL‐13, r=0.52). Conclusions Because cord blood IgE has been shown to be predictive for allergic diseases in early childhood, our results indicate that reduced maternal Treg numbers and increased Th2 cytokine production during pregnancy might influence the allergy risk of the child. Cite this as: D. Hinz, J. C. Simon, C. Maier‐Simon, L. Milkova, S. Röder, U. Sack, M. Borte, I. Lehmann and G. Herberth, Clinical & Experimental Allergy, 2010 (40) 419–426.