Helper Effector Cells Research Articles

Immune cell landscape in symptomatic and asymptomatic SARS-CoV-2 infected adults and children in urban Dhaka, Bangladesh

ObjectivesThe study of cellular immunity to SARS-CoV-2 is crucial for evaluating the course of the COVID-19 disease and for improving vaccine development. We aimed to assess the phenotypic landscape of circulating lymphocytes and mononuclear cells in adults and children who were seropositive to SARS-CoV-2 in the past 6 months. MethodsBlood samples (n = 350) were collected in a cross-sectional study in Dhaka, Bangladesh (Oct 2020-Feb 2021). Plasma antibody responses to SARS-CoV-2 were determined by an electrochemiluminescence immunoassay while lymphocyte and monocyte responses were assessed using flow cytometry including dimensionality reduction and clustering algorithms. ResultsSARS-CoV-2 seropositivity was observed in 52% of adults (18–65 years) and 56% of children (10–17 years). Seropositivity was associated with reduced CD3+T cells in both adults (beta(β) = −2.86; 95% Confidence Interval (CI) = −5.98, 0.27) and children (β = −8.78; 95% CI = −13.8, −3.78). The frequencies of T helper effector (CD4+TEFF) and effector memory cells (CD4+TEM) were increased in seropositive compared to seronegative children. In adults, seropositivity was associated with an elevated proportion of cytotoxic T central memory cells (CD8+TCM). Overall, diverse manifestations of immune cell dysregulations were more prominent in seropositive children compared to adults, who previously had COVID-like symptoms. These changes involved reduced frequencies of CD4+TEFF cells and CD163+CD64+ classical monocytes, but increased levels of intermediate or non-classical monocytes, as well as CD8+TEM cells in symptomatic children. ConclusionSeropositive individuals in convalescence showed increased central and effector memory T cell phenotypes and pro-resolving/healing monocyte phenotypes compared to seronegative subjects. However, seropositive children with a previous history of COVID-like symptoms, displayed an ongoing innate inflammatory trait.

The Amphiregulin/EGFR axis protects from lupus nephritis via downregulation of pathogenic CD4+ T helper cell responses

Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immuno-pathogenesis. Lupus nephritis (LN) is a frequent and difficult to treat complication, which causes high morbidity and mortality. The multifunctional cytokine amphiregulin (AREG) has been implicated in SLE pathogenesis, but its function in LN currently remains unknown. We thus studied the model of pristane-induced LN and found increasing renal and systemic AREG expression during the course of disease. Importantly, renal injury was significantly aggravated in the absence of AREG, revealing a net anti-inflammatory role. Analyses of immune responses showed dual effects. On the one hand, AREG enhanced activation of pro-inflammatory myeloid cells, which however did not play a major role for the course of LN. More importantly, on the other hand, AREG strongly suppressed pathogenic cytokine production by T helper effector cells. This effect was more general in nature and could be reproduced in response to antigen immunization. Since AREG has been postulated to downregulate T cell responses via enhancing Treg suppressive capacity, we followed up on this aspect. Interestingly, however, in vitro studies revealed potential direct and Treg independent effects of AREG on T helper effector cells. In favor of this notion, we found significantly enhanced T cell responses and consecutive aggravation of LN, only if epidermal growth factor receptor (EGFR) signaling was abrogated in total T cells, but not if the EGFR was absent on Tregs alone. Finally, we also found enhanced AREG expression in plasma and renal biopsies of patients with LN, supporting the relevance of our findings for human disease. In summary, our data identify AREG as an anti-inflammatory mediator of LN via broad downregulation of pathogenic T cell immunity. These findings further highlight the AREG/EGFR axis as a potential therapeutic target.

GUT-brain axis

In humans, epidemiological studies suggest that fetuses' exposure to maternal inflammation increases the likelihood of developing Autism Spectrum Disorder (ASD). We previously demonstrated that interleukin-17a (IL-17a) produced by Th17 cells (CD4+ T helper effector cells involved in multiple autoimmune and inflammatory diseases) is required in pregnant mice to induce behavioral abnormalities in offspring exposed to maternal immune activation (MIA). Furthermore, we and others showed that MIA-induced phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation.

Regulation of T Cell Responses by Ionic Salt Signals

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

CD4+ Memory T-Cell Formation during Type 1 Immune Responses.

Naive CD4+ T cells become memory cells after proliferating in response to their cognate major histocompatibility complex class II (MHCII)-bound peptide and passing through an effector cell stage. The process by which CD4+ memory T cells emerge from the effector cell pool, however, is less well understood than in the case of CD8+ T cells. During certain acute infections, naive CD4+ T cells proliferate and differentiate into various forms of type 1 (Th1) and follicular helper (Tfh) effector cells. We review the evidence that about 10% of the cells in each of these subsets survive to become memory cells that resemble their effector cell precursors. The roles that asymmetric cell division, the TCF-1 transcription factor, metabolic activity, reactive oxygen species, and the IL-7 receptor play in the effector to memory cell transition are discussed. We propose a speculative model in which the metabolic activity needed for rapid clonal expansion also generates toxic products that induce apoptosis in most effector cells. Memory cells then arise from the effector cells in each subset that are at the low end of the metabolic activity spectrum.

Biological and clinical significance of T helper 17 cell plasticity.

Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17-derived 'non-classic' Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.

Origins of CD4+ circulating and tissue-resident memory T-cells.

In response to infection, naive CD4+ T-cells proliferate and differentiate into several possible effector subsets, including conventional T helper effector cells (TH 1, TH 2, TH 17), T regulatory cells (Treg ) and T follicular helper cells (TFH ). Once infection is cleared, a small population of long-lived memory cells remains that mediate immune defenses against reinfection. Memory T lymphocytes have classically been categorized into central memory cell (TCM ) and effector memory cell (TEM ) subsets, both of which circulate between blood, secondary lymphoid organs and in some cases non-lymphoid tissues. A third subset of memory cells, referred to as tissue-resident memory cells (TRM ), resides in tissues without recirculation, serving as 'first line' of defense at barrier sites, such as skin, lung and intestinal mucosa, and augmenting innate immunity in the earliest phases of reinfection and recruiting circulating CD4+ and CD8+ T-cells. The presence of multiple CD4+ T helper subsets has complicated studies of CD4+ memory T-cell differentiation, and the mediators required to support their function. In this review, we summarize recent investigations into the origins of CD4+ memory T-cell populations and discuss studies addressing CD4+ TRM differentiation in barrier tissues.

Human Treg Can Suppress Th17 Inflammatory Cytokine Secretion Independent of IL-2 Deprivation

Human Th17 cells are an inflammatory subset of CD4+ (CD4) T helper cells implicated in host of debilitating diseases and disorders such as multiple Sclerosis, rheumatoid arthritis, and psoriasis, as well as inhibitor formation in Hemophilia A. Although it is well established that regulatory CD4T cells (Tregs) can suppress other T helper (Th) effector cells (e.g. Th1, Th2, etc), their ability to suppress human Th17 cells is unresolved. This is attributed to several factors including plasticity between Treg and Th17 cells, the observation that Th17 cells express less IL-2 (and by extension are less dependent on IL-2) than other Th effector cells and consequently are less susceptible to Treg suppression via IL-2 deprivation. Using autologous naïve Tregs and effector memory CCR6+ CD4 T cells differentiated to Th17 cells from healthy human donor peripheral blood mononuclear cells, we performed a kinetic analysis of the IL-2 sensitivity via phosphorylated STAT5 expression. We show that Treg and Th17 cells have similar rates of pSTAT5 expression in vitro. We also show that both cell types have similar expression levels of the high affinity IL-2a receptor, CD25, following activation. Despite this, naïve Tregs successfully abrogated the secretion of IL17A by Th17 cells following 12hr co-culture. Furthermore, this abrogation is dependent on the strength of Treg activation and does not involve cytotoxic mechanisms, as viability of the Th17 cells remain high. These results suggest that human Tregs can suppress inflammatory IL-17A secretion from effector memory Th17 cells via mechanisms independent of IL-2 deprivation but dependent on strength of activation through Treg T-cell receptor. (Supported by NIH grant R01 HL126727) DisclosuresNo relevant conflicts of interest to declare.

Tumor Necrosis Factor Receptor Superfamily in T Cell Priming and Effector Function.

The tumor necrosis factor receptor superfamily (TNFRSF) and their ligands mediate lymphoid tissue development and homeostasis in addition to key aspects of innate and adaptive immune responses. T cells of the adaptive immune system express a number of TNFRSF members that are used to receive signals at different instructive stages and produce several tumor necrosis factor superfamily (TNFSF) members as effector molecules. There is also one example of a TNFRSF member serving as a ligand for negative regulatory checkpoint receptors. In most cases, the ligands in afferent and efferent phases are membrane proteins and thus the interaction with TNFRSF members must take place in immunological synapses and other modes of cell-cell interaction. A particular feature of the TNFRSF-mediated signaling is the prominent use of linear ubiquitin chains as scaffolds for signaling complexes that activate nuclear factor κ-B and Fos/Jun transcriptional regulators. This review will focus on the signaling mechanisms triggered by TNFRSF members in their role as costimulators of early and late phases of T cell instruction and the delivery mechanism of TNFSF members through the immunological synapses of helper and cytotoxic effector cells.

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

Maternal immune activation (MIA) contributes to behavioral abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring1-4. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing Autism Spectrum Disorder (ASD)5-7. We recently demonstrated that interleukin-17a (IL-17a) produced by Th17 cells, CD4+ T helper effector cells involved in multiple inflammatory conditions, is required in pregnant mice to induce behavioral as well as cortical abnormalities in the offspring exposed to MIA8. However, it is unclear if other maternal factors are required to promote MIA-associated phenotypes. Moreover, underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here, we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation. Pregnant mice that had been colonized with the mouse commensal segmented filamentous bacteria (SFB) or human commensal bacteria that induce intestinal Th17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells (DCs) from pregnant, but not from non-pregnant, females upon exposure to MIA secrete IL-1β/IL-23/IL-6 and stimulate T cells to produce IL-17a. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce Th17 cells may increase the risk for neurodevelopmental disorders in offspring of pregnant mothers undergoing immune system activation due to infections or autoinflammatory syndromes.

In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.

CD4+ T cells recruited to the liver play a key role in the pathogenesis of ischemia/reperfusion (I/R) injury. The mechanism of their activation during alloantigen-independent I/R is not completely understood. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4+ T cells in the postischemic liver and that modulation of DCs or T-cell-DC interactions attenuates liver inflammation. In mice, warm hepatic I/R (90/120-240 min) was induced. Tolerogenic DCs were generated in situ by pretreatment of animals with the vitamin D analog paricalcitol. A mAb-CD44 was used for blockade of CD4+ T-cell-DC interactions. As shown by 2-photon in vivo microscopy as well as confocal microscopy, CD4+ T cells were closely colocalized with DCs in the postischemic liver. Pretreatment with paricalcitol attenuated I/R-induced maturation of DCs (flow cytometry), CD4+ T-cell recruitment into the liver (intravital microscopy), and hepatocellular/microvascular damage (intravital microscopy, alanine aminotransferase/aspartate aminotransferase, histology). However, interruption of T-cell-DC interaction increased proinflammatory DC maturation and even enhanced tissue damage. Simultaneous treatment with an anti-CD44mAb completely abolished the beneficial effect of paricalcitol on T-cell migration and tissue injury. Our study demonstrates for the first time that hepatic DCs interact with CD4+ T cells in the postischemic liver in vivo; modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4+ T-cell recruitment and reduces I/R injury; and interruption of CD44-dependent CD4+ T-cell-DC interactions enhances tissue injury by preventing the modulatory effect of hepatic DCs on T cells, especially type 1 T helper effector cells. Thus, hepatic DCs are strongly involved in the promotion of CD4+ T-cell-dependent postischemic liver inflammation.-Funken, D., Ishikawa-Ankerhold, H., Uhl, B., Lerchenberger, M., Rentsch, M., Mayr, D., Massberg, S., Werner, J., Khandoga, A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver.

T1/ST2 deficient mice display protection against Leishmania infantum experimental infection

T1/ST2 is a surface marker selectively expressed on type 2 helper (TH2) effector cells. As Leishmania infection in susceptible BALB/c mice have ascribed to a polarized TH2 response, this study aim to investigate the T1/ST2 (the receptor for IL-33), as a typical TH2 marker in the postulation that a shift towards a beneficial TH1 response would occur in the absence of ST2. For this, ST2 knockout (ST2−/−) and WT BALB/c mice were experimentally infected in the retro-orbital sinus with L. infantum. We showed that ST2−/− animals displayed better control of parasite burden in both spleen and liver tissues at different time points of chronic phases, and reduced spleenomegaly and hepatomegaly compared with the wild-type (WT) mice. This was associated with increased in the IFN-γ levels and expression by CD4+ and CD8+ lymphocytes. The inflammatory response encompasses transaminases (AST and ALT) releases and NO productions were remarkably lower in ST2−/− mice compared with WT. These data suggest that, ST2−/−) exert protection against L. infantum infection and probably shift the immune response toward TH1 induction.

Impact of Enriched Environment on Murine T Cell Differentiation and Gene Expression Profile.

T cells are known to be plastic and to change their phenotype according to the cellular and biochemical milieu they are embedded in. In this study, we transposed this concept at a macroscopic level assessing whether changes in the environmental housing conditions of C57/BL6 mice would influence the phenotype and function of T cells. Our study shows that exposure to 2 weeks in an enriched environment (EE) does not impact the T cell repertoire in vivo and causes no changes in the early TCR-driven activation events of these cells. Surprisingly, however, T cells from enriched mice showed a unique T helper effector cell phenotype upon differentiation in vitro. This was featured by a significant reduction in their ability to produce IFN-γ and by an increased release of IL-10 and IL-17. Microarray analysis of these cells also revealed a unique gene fingerprint with key signaling pathways involved in autoimmunity being modulated. Together, our results provide first evidence for a specific effect of EE on T cell differentiation and its associated changes in gene expression profile. In addition, our study sheds new light on the possible mechanisms by which changes in environmental factors can significantly influence the immune response of the host and favor the resolution of the inflammatory response.

Differential regulation of TH1, TFH, and TCM gene programs by cytokine-mediated events

Abstract During the course of an immune response, multiple effector T helper cell types emerge to combat the initial infection, with subsequent emergence of long-term CD4+ T memory cells to ensure that a second exposure to the same pathogen will not cause disease. CD4+ T helper cell populations that are critical for this process include T helper 1 (TH1) and T follicular Helper (TFH) effector cells and long-lasting central memory T (TCM) cells. Previous work has demonstrated a level of flexibility between effector TH1 and TFH-like cell populations, with the respective gene programs regulated by alterations in interleukin 2 (IL-2) signaling. Here, we demonstrate that in response to decreased IL-2 signaling, effector TH1 cells are capable of initiating the expression of both TFH and TCM-like gene programs, including cell surface expression of IL-6Ra and IL-7R. Importantly, exposure of these cells to either IL-6 or IL-7 augments or inhibits the TFH gene program, respectively, suggesting a potential mechanism whereby cytokine availability may influence TFH or TCM cell function. Consistent with this model, we have identified a novel population of IL-6Ra+IL-7R+ cells that emerge at late time points post-infection in an in vivo mouse model of influenza infection. Further research into the temporal and spatial expression of IL-2, IL-6, and IL-7 in the modulation of these cells represents an exciting avenue of research with wide-ranging therapeutic implications.

IL-6 induces IL-21 and B cell helper function in CD8 cells

Abstract Interleukin 6 (IL-6) is a pro-inflammatory produced by various cell types in response to external stimuli including trauma, stress and infection. IL-6 signaling plays an important role in immune reaction and progression of several autoimmune diseases by programing CD4 cell differentiation and effector functions. CD8 cells was first believed to primarily function as cytotoxic effector cells, their helper cell effector function has been better understood till recently. During activation, CD8 cells can be primed in different cytokine environments to differentiate into different CD8 effector subtypes, including Tc1, Tc2 and recently identified Tc17. Although the role of IL-6 in CD4 cell differentiation and effector function is well known, how IL-6 may regulate CD8 cell differentiation is less studied. In this study, we show that IL-6 induces IL-21 production in CD8 cells during activation through the transcription factor Stat3. Importantly, IL-6 also differentiates CD8 cells to an effector subset producing high IL-21 but low IFN-γ and IL-2. IL-6R expression level in CD8 cells determines the subset of cells that capable of making IL-21. Similar to IL-21 producing CD4 cells, surprisingly, IL-21 producing CD8 cells provides B cell help by inducing isotype switching and promoting antibody production in vitro and in vivo during influenza A flu infection. Thus, our study suggests that IL-6 could differentiate CD8 cells into IL-21 producing B cell helper subset that may play a unique role in restricting infection and the progression of autoimmune diseases.

CD4+ T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes.

Multiple studies have identified CD4+ T cells as central players of glomerulonephritis (GN). Cells of the Th1 and Th17 responses cause renal tissue damage, while Tregs mediate protection. Recently, a high degree of plasticity among these T cell lineages was proposed. During inflammation, Th17 cells were shown to have the potential of transdifferentiation into Th1, Th2, or alternatively anti-inflammatory Tr1 cells. Currently available data from studies in GN, however, do not indicate relevant Th17 to Th1 or Th2 conversion, leaving the Th17 cell fate enigmatic. Tregs, on the other hand, were speculated to transdifferentiate into Th17 cells. Again, data from GN do not support this concept. Rather, it seems that previously unrecognized subspecialized effector Treg lineages exist. These include Th1 specific Treg1 as well as Th17 directed Treg17 cells. Furthermore, a bifunctional Treg subpopulation was recently identified in GN, which secrets IL-17 and coexpresses Foxp3 together with the Th17 characteristic transcription factor RORγt. Similarities between these different and highly specialized effector Treg subpopulations with the corresponding T helper effector cell lineages might have resulted in previous misinterpretation as Treg transdifferentiation. In summary, Th17 cells have a relatively stable phenotype during GN, while, in the case of Tregs, currently available data suggest lineage heterogeneity rather than plasticity.

ID: 156: Transcriptional control of innate lymphoid cell fate decisions

Innate lymphoid cells (ILCs) are a recently discovered family of innate lymphocytes that are substantially represented at mucosal surfaces and have been implicated in the protection of epithelial barriers. Various types of ILCs can be discriminated based on the expression of distinct transcription factors controlling the expression of a distinct set of cytokine genes endowing the various ILC subsets with a specific range of effector functions. Currently, three groups of ILCs are being recognized. Group 1 ILCs (ILC1s) are a diverse group of ILCs comprised of natural killer (NK) cells and other, poorly defined subsets of ILCs. It is believed that the ILC1 fate decision is controlled by the T-box transcription factor T-bet endowing ILC1s with the capability to produce large amounts of IFN- γ . ILC2s express high levels of GATA-3, produce IL-5 and IL-13 and have been involved in immunity to helminth infections and in the pathogenesis of allergic diseases. Group 3 ILCs developmentally depend on the transcription factor ROR γ t and produce the cytokines IL-22, IL-17A and IL-17F. ILC3s are believed to be involved in the protection against intestinal bacterial infections and, if inappropriately stimulated, can be important drivers of inflammatory disorders. The transcriptional programs and effector cytokines of the various ILC subsets strikingly resemble those of the various T helper cell effector fates suggesting that such transcriptional circuitry already formed in the evolutionary older innate immune system. The various ILC subsets are developmentally related as all ILC lineages depend on the transcriptional regulator Id2 (inhibitor of DNA binding 2) that interfers with E2 protein-controlled gene expression. This raises the important issue if ILCs may derive from a common ILC progenitor (CILP). Identification of such a progenitor would allow to identify the molecular signals required for the specification of the various ILC lineages. I will discuss progress towards our understanding of the molecular programs regulating ILC fate decisions and our current models of transcriptional stability and plasticity of ILC fates. Finally, I will discuss an unprecedented role of ILC3s in the protection against mucosal virus infections. Research in my lab is supported by grants from the European Research Council (ERC) and Deutsche Forschungsgemeinschaft.

A non-cytolytic role for NK cells during gp96-mediated immunotherapy (VAC13P.1129)

Abstract Immunogenic Heat Shock Proteins (HSPs) are capable of eliciting potent immune responses against their chaperoned antigens and are being investigated as a potential cancer immunotherapy. The current model of HSP mediated immune responses includes roles for Dendritic Cells (DCs) and T cells in priming and executing the HSP-mediated response. Additionally, NK cells are necessary to inhibit tumor growth following immunotherapy with HSPs. NK cells are innate lymphoid cells whose effector functions include cytokine production and target cell lysis. Despite their requirement, little is known about what role(s) NK cells play in HSP-mediated immune responses. In these studies, we aim to determine if NK cells are acting as helper cells or effector cells using the prototypical immunogenic HSP, gp96. Our results demonstrate that depletion of NK cells specifically during the effector phase (post-gp96 immunization) results in a loss of control of D122 tumor growth. Interestingly, NK cells isolated from mice immunized with gp96 do not exhibit increased killing ex vivo, suggesting NK cells may be acting as helper cells instead of directly killing tumor cells. Additionally, we determined that NK cells improve DC activation in response to gp96 in vitro, suggesting NK cells may also play a role in priming HSP-mediated T cell responses. Collectively, these data indicate that HSP-activated NK cells are capable of acting as helper cells, potentially during multiple stages of the immune response.

Human Th1 dichotomy: origin, phenotype and biologic activities.

The great variety of pathogens present in the environment has obliged the immune system to evolve different mechanisms for tailored and maximally protective responses. Initially, two major types of CD4+ T helper (Th) effector cells were identified, and named as type 1 (Th1) and type (Th2) cells because of the different cytokines they produce. More recently, a third type of CD4+ Th effectors has been identified and named as Th17 cells. Th17 cells, however, have been found to exhibit high plasticity because they rapidly shift into the Th1 phenotype in the inflammatory sites. Therefore, in these sites usually there is a dichotomic mixture of classic and non classic (Th17-derived) Th1 cells. In humans, non classic Th1 cells express CD161, as well as the retinoic acid orphan receptor C, IL-17 receptor E, IL-1RI, CCR6, and IL-4-induced gene 1 and Tob-1, which are all virtually absent from classic Th1 cells. The possibility to distinguish these two cell subsets may allow the opportunity to better establish their respective pathogenic role in different chronic inflammatory disorders. In this review, we discuss the different origin, the distinctive phenotypic features and the major biologic activities of classic and non classic Th1 cells. This article is protected by copyright. All rights reserved.

Differential immune responses to excretory–secretory antigens of lung-stage larvae of Schistosoma mansoni in mice and rats

In contrast to mice, rats are less-susceptible to infection with Schistosoma mansoni, perhaps mounting protective immune responses that provide a microenvironment unfavorable for the normal growth and survival of the parasite. Upon infection, schistosomular excretory–secretory products (ESP) trigger T helper (Th) effector cells and polarize the immune microenvironment. We investigated the differences in mouse and rat immune responses to the larval ESP, 14-3-3-like protein, P18, and fructose-1,6-bisphosphate aldolase, prepared in a recombinant or multiple antigen peptide form. Ex vivo spleen cells (SC) of naïve, and 7day-S. mansoni-infected CD1 mice and Wistar rats were stimulated in vitro with the selected ESP, and the culture supernatants were assessed for cytokine levels by capture enzyme-linked immunosorbent assay. S. mansoni ESP failed to induce SC of 7day-infected mice to produce detectable interleukin (IL)-4 levels, but led to significant increase in released interferon-gamma (IFN-γ) as compared to naïve mice. Conversely, SC of rats released significant IL-4 levels in response to ESP stimulation, while IFN-γ was hardly detected in the supernatants. Amounts of ESP-specific antibodies in infected rats were significantly higher than in infected mice. Our results suggest that resistance to schistosomiasis is associated with type 2 cytokines and high levels of parasite ESP-specific antibodies.