T-helper Populations Research Articles

Age-Related Changes in the Clustering of Blood Populations in Cynomolgus Monkeys Depend on Sex and Immune Status.

Non-anthropoid primates cynomolgus monkeys (Macaca fascicularis), also known as crab-eating macaques, are increasingly used in biomedical and preclinical studies due to their evolutionary proximity to humans, sharing similar diets, infectious and senile diseases. Age-related changes and sexual dimorphism of the immune system of C. monkeys have not been sufficiently characterized in literature, though age and sex differences affect the course of diseases and sensitivity to medications. Aging in C. monkeys is accompanied by an increase in CD3+CD4+CD8+ (DP-T) cells, plasma B-cells, and a decrease in platelets. Erythromyeloid bias has also been noticed in older animals. There was an increase in eosinophils, haematocrit (HCT) and haemoglobin concentration (HGB). Senile decline in the function of the immune system had sex differences. An increase in the number of monocytes, cytotoxic lymphocytes (CTL) and a decrease in the T-helper population were more pronounced in older females. A significant reduction in the number of B-cells and activated T-cells was detected in males only. A moderate correlation with the regression model of aging was established for DP-T, HCT and HGB. The reduction in the B cells count in males and the increase in CTL level in females are moderately correlated with age. Other blood cell populations did not show significant correlations in the regression models due to their high sample variability. The novel cell population CD3-CD20loCD16/CD56+, presumably NK-cells subset, was revealed. This cell population demonstrated an increase trend with age in both sexes. Population-statistical age norms for different sexes for young and very old macaques were established. The blood population clusters associated with sex and immune status in older animals were also identified.

Hemizygous nonsense variant in the moesin gene (MSN) leads to a new autoimmune phenotype of Immunodeficiency 50.

Here, we present the findings of an investigation involving two male siblings with juvenile total tooth loss, early-onset chronic leg ulcers, and autoimmune thyroiditis, as well as focal segmental glomerulosclerosis with associated pulmonary emphysema in one and diabetes mellitus in the other. The clinical picture and lupus anticoagulant, cryoglobulin, and cold agglutinin positivity suggested the diagnosis of antiphospholipid syndrome. Flow cytometry analysis showed immunophenotypes consistent with immune dysregulation: a low number of naive T cells, elevated CD4+ T cell counts, and decreased CD8+ T-cell counts were detected, and more than half of the T-helper population was activated. Considering the siblings’ almost identical clinical phenotype, the genetic alteration was suspected in the background of the immunodeficiency. Whole exome sequencing identified a previously not described hemizygous nonsense variant (c.650G>A, p.W217X) within exon 6 of the moesin (MSN) gene localized on chromosome X, resulting in significantly decreased MSN mRNA expression compared to healthy controls. We present a putative new autoimmune phenotype of Immunodeficiency 50 (MIM300988) characterized by antiphospholipid syndrome, Hashimoto’s thyroiditis, leg ulcers, and juvenile tooth loss, associated with W217X mutation of the MSN gene.

Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes.MethodsEighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells.ResultsThe overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm3, p < 0.0001), correlated with age (r = − 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm3, p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002).ConclusionsOur findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection.

Cell Differentiation Degree as a Factor Determining the Role for Different T-Helper Populations in Tuberculosis Protection.

Efficient tuberculosis (TB) control depends on early TB prediction and prevention. Solution to these tasks requires knowledge of TB protection correlates (TB CoPs), i.e., laboratory markers that are mechanistically involved in the protection and which allow to determine how well an individual is protected against TB or how efficient the candidate TB vaccine is. The search for TB CoPs has been largely focused on different T-helper populations, however, the data are controversial, and no reliable CoPs are still known. Here we discuss the role of different T-helper populations in TB protection focusing predominantly on Th17, “non-classical” Th1 (Th1*) and “classical” Th1 (cTh1) populations. We analyze how these populations differ besides their effector activity and suggest the hypothesis that: (i) links the protective potential of Th17, Th1*, and cTh1 to their differentiation degree and plasticity; (ii) implies different roles of these populations in response to vaccination, latent TB infection (LTBI), and active TB. One of the clinically relevant outcomes of this hypothesis is that over-stimulating T cells during vaccination and biasing T cell response toward the preferential generation of Th1 are not beneficial. The review sheds new light on the problem of TB CoPs and will help develop better strategies for TB control.

Compartmentalization of dendritic cell and T-cell interactions in the lymph node: Anatomy of T-cell fate decisions.

Upon receiving cognate and co-stimulatory priming signals from antigen (Ag)-presenting dendritic cells (DCs) in secondary lymphoid tissues, naïve CD4+ T cells differentiate into distinct effector and memory populations. These alternate cell fate decisions, which ultimately control the T-cell functional attributes, are dictated by programming signals provided by Ag-bearing DCs and by other cells that are present in the microenvironment in which T-cell priming occurs. We know that DCs can be subdivided into multiple populations and that the various DC subsets exhibit differential capacities to initiate development of the different CD4+ T-helper populations. What is less well understood is why different subanatomic regions of secondary lymphoid tissues are colonized by distinct populations of Ag-presenting DCs and how the location of these DCs influences the type of T-cell response that will be generated. Here we review how chemokine receptors and their ligands, which position allergen and nematode-activated DCs within different microdomains of secondary lymphoid tissues, contribute to the establishment of IL-4 committed follicular helper T and type 2 helper cell responses.

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome.

We previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors. To verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients. Monocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) α and GRβ, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage. As compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRα and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found. T cell deficits most likely are a trait phenomenon of BD, since they have also been found in the other cohorts of BD patients and in bipolar offspring. Monocytes of this cohort showed an anti-inflammatory set point, suggesting that pro- and anti-inflammation are state characteristics of BD. The monocyte gene profile indicated an increased CAC activity; the question arises whether this is due to putative vessel damage in these relatively old patients with a high prevalence of the MetS.

Blinatumomab + Tyrosine Kinase Inhibitors in the Treatment of Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Patients - Clinical Efficacy and Peripheral Blood Lymphocytes Subpopulations Kinetics

▪Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody. It showed efficacy as a single agent in the treatment of relapsed/refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). T-regulatory (T-reg) and T-helper cells can inhibit effector T-cells used by blinatumomab. Tyrosine-kinase inhibitors (TKI) are the basic treatment of the Ph+ ALL. To improve the long-term results of the relapsed Ph+ ALL treatment we combined blinatumomab with TKIs dasatinib or nilotinib or ponatinib.The aim of this study was to evaluate clinical efficacy of blinatumomab + TKI combination in relapsed Ph+ ALL patients and to study T-cell and NK subpopulations kinetics in R/R-ALL patients during the treatment.From Oct 2015 to June 2016 we treated 6 relapsed Ph+ ALL patients (5 overt hematological relapses and 1 cytogenetic relapse). Blinatumomab was administered in the dose 28 mcg/day by continuous IV infusion 28 days (4 week cycle) with 2 weeks intervals (up to 4 cycles). The dose of blinatumomab in the 1st week of the 1st cycle was 9 mcg/day. Dasatinib 140 mg/day PO started on 1 week and administered daily continuously. Nilotinib 400 mg bid PO was administered in the case of dasatinib toxicity. Ponatinib 45 mg /day PO was administered in the case of T315I ABL kinase domaine mutation. Lymphocytes subpopulations of the peripheral blood (T-helper CD3+/CD4+/CD8-, T-cytotoxic CD3+/CD4-/CD8+, T-reg CD3+/CD4+/CD25+, NK CD3-/CD56+) were studied by flow cytometry on the 1st day of every week during every blinatumomab cycle.Two pts received all 4 cycles of blinatomomab + TKI dasatinib (two MolCR after 2nd cycle). Two pts received 2 cycles of blinatumomab + TKI dasatinib (two MolCR) and are continuing treatment. 1 pt with T315I mutation received 1 cycle of blinatumomab + TKI ponatinib (MolCR). 1 pt progressed during 1st cycle of blinatumomab + dasatinib which were discontinued. AlloBMT was performed in 2 pts in MolCR and 3 pts in MolCR are awaiting alloBMT. All 6 pts are alive. The pt who progressed on the 1-st cycle of blinatumomab + dasatinib was later diagnosed with T315I mutation and CR was obtained on ponatinib + dexamethasone + vincristine. In 1 pt the dasatinib-related pleural effusions and lung infiltration observed which fully regressed after 2 weeks of dasatinib interruption. Dasatinib in that pt was later replaced with nilotinib during 4th cycle and so on. Hypogammaglobulinemia was common and corrected with intravenous human normal immunoglobulin replacement. No neurological toxicity observed. As a result, 5 MolCR were obtained in 6 pts who received blinatumomab + TKI except in 1 pt with T315I mutation who progressed on blinatumomab + dasatinib. In all pts T-helper population was about low limit of normal range or below it (Fig. 1). In 4 of 5 responded pts the restoration of cytotoxic T-cell subpopulation was observed (Fig. 2). In 4 of 5 responded pts the 2nd week T-reg dropping occurred (Fig. 3). In all of responded pts NK population returned to normal range.The blinatumomab + TKI combination is effective in relapsed Ph+ ALL. The MolCR obtaining is possible without glucocorticoid treatment. The combination has acceptable toxicity. The T-reg subpopulation depletion on 2 week and depleted pool of T-helper are correlated with MolCR obtaining during blinatumomab + TKI treatment. The T cell cytotoxic and NK lymphocyte subpopulation restoring possibly reflects normal hemopoiesis establishing in MolCR settings in effectively treated pts. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois

CRSsNP is a heterogenous disease but type 2 inflammation in CRSsNP was more common than type 1 inflammation among patients in Chicago, Illinois. Distinct therapeutic strategies may be needed depending on the type of inflammation found in CRSsNP.

CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm.

CD4(+)T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4(+)T-cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model--the pathogenic T-helper population disease-induction model--as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.

Regulation of immune responses by interleukin‐27

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including autoimmunity. Recently, interleukin-27 (IL-27) was identified, which, along with IL-12, IL-23, and IL-35, belongs to the IL-12 cytokine family. These family members play roles in the regulation of T helper (Th) cell differentiation. IL-27 is unique in that while it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyper-production of various pro-inflammatory cytokines concomitant with severe inflammation in affected organs was observed in IL-27 receptor alpha chain (WSX-1)-deficient mice infected with Trypanosoma cruzi. Experimental allergic or inflammatory responses were also enhanced in WSX-1-deficient mice. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells (a newly identified inflammatory T-helper population) and induction of IL-10 production. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies on the role of IL-27 in immunity to parasitic and bacterial infections as well as in allergy and autoimmunity in view of its pro- and anti-inflammatory properties.

Induction of abortive and productive proliferation in resting human T lymphocytes via CD3 and CD28.

How the T-cell receptor (TCR)/CD3 complex mediates positive as well as negative signals for T-cell regulation is not fully understood. We have previously described the induction of anergy in resting human T lymphocytes after mitogenic, high-dose CD3 triggering with monoclonal antibodies. Here we report the concomitantly occurring cell death to be largely caused by apoptosis, which mainly affects the CD4+ T-helper population. Because cell death becomes detectable after initial cell proliferation, it appears that a high-dose CD3 stimulus constitutes a negative signal for resting T cells leading to an 'abortive proliferation' that is followed by anergy and/or apoptosis of the cells. In contrast, if initial proliferation is induced by a low dose of anti-CD3 in the presence of an accessory signal via the CD28 receptor, anergy and cell death are markedly reduced and 'productive proliferation' may occur. Productive proliferation is characterized by an increased secretion of various cytokines measured (interleukin (IL)-2, IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma)). A low-dose submitogenic CD3 stimulus induced neither anergy nor cell death, supporting the view that negative CD3 signalling requires proliferation of resting cells.

L3T4+ but not LYT2+ T-helper cells are required for in vitro maturation of in vivo primed T cells in the cytotoxic response to MHC class I disparate cells following footpad immunization.

The induction characteristics of major histocompatibility complex (MHC) class I-specific cytotoxic T lymphocytes (CTL) after footpad immunization were studied. Primary CTL were generated in the regional lymph nodes of C57Bl/6 mice by footpad injection with 10(7) irradiated (2000 rad) spleen cells from MHC class I mutant mouse strain (bm1) followed by a short in vitro culturing without antigen. The requirement of accessory cells and L3T4+ T cells during in vitro maturation of in vivo primed CTL precursor (CTLp) was shown. Moreover, using inhibitory antibodies, the need for IL-2 and IL-4 for in vitro maturation of CTL was established. We have suggested that accessory cells act at the level of L3T4+ T cells which in turn non-specifically up-regulate the CTL response through the production of growth and differentiation factors. Thus, the T-helper population of L3T4+ but not Lyt2+ phenotype appears to be recruited in the in vitro maturation of in vivo primed CTLp in a given system. Possible mechanisms of this phenomenon are discussed.

Upregulation of lymphocyte β-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit

To test the hypothesis of an altered central nervous system influence upon the immune system of Down's syndrome (DS) patients and in order to establish a peripheral biological marker of neuroimmune deficit, we have studied the characteristics of the β 2-adrenergic receptor (B 2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals and correlated alterations in binding with changes in distribution of lymphocyte subsets. Using the very potent β-adrenergic antagonist, iodocyanopindolol ([ 125I]CYP), as a ligand, the present study shows that a typical BAR population of the β 2-subtype is present in PBMC from DS children, with binding kinetics and structural specificity similar to those measured in PBMC from patients with other (non-genetic) forms of mental retardation, or in PBMC from age-matched healthy subjects. On the other hand, this study revealed a significance increase in B 2AR binding capacity of PBMC from DS subjects ( B max = 5258 ± 470 sites/cell) compared to the values measured in the control population of retarded children ( B max = 1965 ± 280 sites/cell), characterized by an approximately three-fold increase in the B max, without changes in binding affinity ( K D = 40.5 ± 2.0 and 36.6 ± 2.5 pM in DS and retarded patients, respectively). The flowcytometric markers revealed a profound alteration in the distribution of lymphocyte subtypes with an almost 50% decrease in B cell and T-helper populations, a three-fold increase in T-cytotoxic suppressor, a seven-fold increase in lymphocyte-activated killer cells (LAK) and 30% increase in natural killer (NK) subpopulations. When fluorescence-labelled lymphocytes were visualized in the cytofluorograph and sorted for their use in the radioreceptor assay, B cells had approximately twice the number of B 2AR when compared to T cells; and cytotoxic/suppressor showed a higher binding capacity compared to T-helper cells. On the other hand, labelled lymphocytes from DS patients showed a specific increase in receptor number in B cells, T-cytotoxic suppressor and NK subpopulations. It is concluded that a profound catecholaminergic dysfunction not previously appreciated in DS is reflected by a significant alteration in lymphocyte subset distribution and by a specific up-regulation of lymphocyte B 2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon. From the present data it seems tempting to speculate that the B 2AR might represent a valuable marker of neuroimmune dysfunction in DS and possibly other brain pathologies.

Role of the mononuclear phagocyte system in the development of acquired immunodeficiency syndrome (AIDS).

This review describes current understanding of the role of cells of the mononuclear phagocyte system in the development of acquired immunodeficiency syndrome (AIDS). Monocyte-macrophage like cells have been shown to harbor human immunodeficiency virus type 1 (HIV-I) infection in both peripheral blood and bone marrow as well as in target organs such as brain, lungs, lymph nodes, and skin. Mononuclear phagocytes that have been infected by HIV-I do not undergo significant cytopathic changes, suggesting that they may be important viral reservoirs. These and related cells may also promote the slow, persistent nature of HIV-I infections by escaping host immunologic surveillance mechanisms. There is evidence that HIV-I infections in monocytes and premonocytes can initially be latent but progress to an active viral replication state upon differentiation and/or maturation. Functional abnormalities in the mononuclear phagocyte system following infection by HIV-I have also been described, and these may be partially responsible for the severe immunosuppression characteristic of AIDS and AIDS-related disorders. These defects may be mediated by quantitative and qualitative changes in the T-helper population. Although the role of mononuclear phagocytes as viral reservoirs and as mediators of immunosuppression is still largely speculative, increasing evidence suggests that these cells influence the course of HIV-I infections.

The prognosis of asymptomatic homosexual men with decreased T-helper to T-suppressor ratio.

Screening of 70 asymptomatic homosexual men in Copenhagen revealed that 13 (19%) had T-helper to T-suppressor (H/S) ratios less than or equal to 1.0. Clinical and immunological follow-up examinations for 2-7 months (mean, 5.2 months) disclosed that none of the 13 men developed the acquired immunodeficiency syndrome (AIDS) or AIDS-like symptoms. An increase in H/S ratios to greater than 1.0 was observed in 11 of the 13 men during the time of observation. The decreased H/S ratios were due to an increase in the T-suppressor population. The T-helper population did not at any time differ from that found in 31 male control subjects. The biological relevance of the observed decrease in H/S ratios was supported by the demonstration of a positive correlation to a decrease in the proliferative response of the lymphocytes. Serological studies did not reveal any specific infectious background for the low H/S ratio found in the 13 men, and the reason for the 'spontaneous' increase during the time of observation remains unknown. The present results indicate that most asymptomatic homosexual men with a decreased H/S ratio will experience normalization of the immunological variables.