Altered T-cell Responses Research Articles

SARS-CoV-2 infection elucidates features of pregnancy-specific immunity

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered Tcell responses in pregnant women, including a clonal expansion of CD4-expressing CD8+ Tcells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive Tcell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection.

COVID-19 vaccination induces distinct T-cell responses in pediatric solid organ transplant recipients and immunocompetent children

Immune responses to COVID-19 vaccination are attenuated in adult solid organ transplant recipients (SOTRs) and additional vaccine doses are recommended for this population. However, whether COVID-19 mRNA vaccine responses are limited in pediatric SOTRs (pSOTRs) compared to immunocompetent children is unknown. Due to SARS-CoV-2 evolution and mutations that evade neutralizing antibodies, T cells may provide important defense in SOTRs who mount poor humoral responses. Therefore, we assessed anti-SARS-CoV-2 IgG titers, surrogate neutralization, and spike (S)-specific T-cell responses to COVID-19 mRNA vaccines in pSOTRs and their healthy siblings (pHCs) before and after the bivalent vaccine dose. Despite immunosuppression, pSOTRs demonstrated humoral responses to both ancestral strain and Omicron subvariants following the primary ancestral strain monovalent mRNA COVID-19 series and multiple booster doses. These responses were not significantly different from those observed in pHCs and significantly higher six months after vaccination than responses in adult SOTRs two weeks post-vaccination. However, pSOTRs mounted limited S-specific CD8+ T-cell responses and qualitatively distinct CD4+ T-cell responses, primarily producing IL-2 and TNF with less IFN-γ production compared to pHCs. Bivalent vaccination enhanced humoral responses in some pSOTRs but did not shift the CD4+ T-cell responses toward increased IFN-γ production. Our findings indicate that S-specific CD4+ T cells in pSOTRs have distinct qualities with unknown protective capacity, yet vaccination produces cross-reactive antibodies not significantly different from responses in pHCs. Given altered T-cell responses, additional vaccine doses in pSOTRs to maintain high titer cross-reactive antibodies may be important in ensuring protection against SARS-CoV-2.

VapC12 ribonuclease toxin modulates host immune response during Mycobacterium tuberculosis infection.

Mechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12 induced a pro-inflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12 succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12 was dependent on the presence of the TLR4 receptor. Overall, the data suggests that failure of a timely resolution of the early inflammation by the ΔvapC12 infected mice led to hyperinflammation, altered T-cell response and high bacterial load. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the innate immune response of the host in ways that favor the long-term survival of the pathogen inside the host.

Altered T-Cell Profile in Sickle Cell Disease

Background: Impaired immune status due to altered T-cell response in sickle cell disease (SCD) might provide substantial insight into immune activity in SCD patients. Materials & methods: A total of30 healthy control, 20 SCD patients in a crisis state and 38 SCD patients in a steady state were evaluated for T-cell subsets. Results: A significant decrease in CD8+ (p=0.012) and CD8+45RA-197+ (p=0.015) T-cells were observed among SCD patients. Naive T-cells(45RA+197+;p<0.01) were elevated and effector (RA-197-) and central memory (RA-197+) T-cells were grossly reduced in the crisis state. Negative regression of naive T-cells with CD8+57+ affirmed immune inactivation. The predictor score reflected 100% sensitivity for predicting the crisis state (area under the curve=0.851; p<0.001). Conclusion: Monitoring naive T-cells with predictive scores can help assess the early shift from a steady state to a crisis state.

Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce Tcell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered Tcell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates Tcells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate Tcells, highlighting a new approach to enhance the efficacy of immunotherapies.

Clinical relevance and therapeutic aspects of professional antigen-presenting cells in lung cancer.

Lung cancer stays the preeminent cause of death worldwide. Despite recent advancements in chemotherapy, radiotherapy, and immunotherapy, the survival rate for people with advanced stages of the disease is still appalling. Moreover, there is a severe lack of reliable prognoses and indicators for classification in newly developed immunotherapies. A better understanding of immune cells is necessary to harness immune response mechanisms for therapeutic effects. Professional antigen-presenting cells are responsible for determining the fate of the immune response through the antigen processing and presentation pathway (APP). The most professional antigen-presenting cells (APC) include the dendritic cells (DC), macrophages, and B cells, which present antigens to the T-helper cells. Dendritic cells are significantly explored as a tool for immunotherapy owing to their precise ability to provoke and alter T-cell responses. Moreover, the role of tumor-associated macrophages (TAMs), an abundant leukocyte in lung cancer, is also a potential target for adjuvant anti-cancer therapies. In this review, we summarize the recent advances in our understanding of the various types of immunotherapy mapped out via professional antigen-presenting cells in lung cancer.

Rise and exacerbation of oral lichen planus in the background of SARS-CoV-2 infection

Oral Lichen Planus (OLP) is a chronic inflammatory disorder whose exact etiology remains unknown. Inflammatory mediators, cytotoxic CD8+ T cells and mast cells have been hypothesized to mediate the pathogenesis of OLP. COVID-19 pandemic caused by SARS-CoV-2 is marked by cytokine storms in the affected patients. Altered T-cell responses marked by exhaustion of T-cell count with hyperaggressive remaining T-cells and presence of cross-reactive antibodies render infected humans as fertile grounds for development of multisystem disorders. In addition, Vitamin D deficiency in COVID-19 patients can further modify the T cell mediated immunity. Increased circulating cytokines and hyperactive CD8+ T cells can alter the oral immune barriers rendering them susceptible to oral disorders. Due to the widespread immune dysregulation, it is possible that patients of COVID-19 may develop OLP in the aftermath or during recovery. The paper explores the pathogenic mechanism behind development OLP as post-COVID condition on account of their target receptor, T-cell responses, cytokine profile, mucosal immune barriers and nutrition deficiency.

IL-22 production of effector CD4+ T-cells is altered in SLE patients

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134+ and PD-1+ T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134+ and PD-1+CD4+ T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients.MethodsPeripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134+ and PD-1+ T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index.ResultsPeripheral unstimulated CD134+ and PD-1+ CD4+ T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134+ and PD-1+ CD4+ T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134+CD4+ T-cells were also significantly decreased in SLE as compared to HC.ConclusionCD134+ and PD-1+CD4+ T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.

B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

AbstractThe Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by Aicda gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8+ T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD8+ T cells specific for inoculated tumor cells, suggesting impaired antitumor T-cell activity. Gene-expression microarray revealed that altered T-cell responses were due to increased IL-33 production by Notch1-activated B cells. Knockout of IL33 or blockade of IL-33 by a receptor-blocking antibody abrogated the Treg and Th2 cell–dominant T-cell response triggered by B cells. Gene-expression data derived from human diffuse large B-cell lymphoma (DLBCL) samples showed that an activated Notch-signaling signature correlates positively with IL33 expression and Treg cell–rich gene-expression signatures. These findings indicate that B cells harboring dysregulated Notch signaling alter T-cell responses via IL-33, and suggest that aberrant activation of Notch signaling plays a role in fostering immune privilege in mature B-cell neoplasms.

The phenolic fraction of extra virgin olive oil modulates the activation and the inflammatory response of T cells from patients with systemic lupus erythematosus and healthy donors

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease characterized by immune deregulation, which involves altered T-cell response and imbalance of cytokine production. The phenolic fraction (PE) of extra virgin olive oil (EVOO) possesses anti-inflammatory and immunomodulatory properties and exerts preventive effects in murine models of immune-inflammatory diseases, such as SLE. The present study was designed to determine the in vitro effects of the PE from EVOO on peripheral blood mononuclear cells (PBMC) from inactive patients with SLE and healthy donors. T-cell phenotype was investigated by flow cytometry, cytokine levels were determined by ELISA, and protein expression was detected by Western blot. The PE of EVOO decreased the frequency of CD69+ cells and the secretion of IFN-γ, TNF-α, IL-6, IL-1β, and IL-10. Moreover, PE increased the expression of I-kappa-B-α and decreased extracellular signal regulated kinase phosphorylation on PBMC from patients with SLE and healthy donors. PE modulates cytokine production and attenuates induced T-cell activation, probably through NF-κB signaling pathway, providing the first evidence that PE from EVOO has an anti-inflammatory and immunomodulatory role in SLE patients and it might therefore be considered as a dietary complement in SLE management.

Impact of hyperlipidemia on alloimmunity.

Hyperlipidemia is a comorbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently, it has been shown that hyperlipidemia can significantly alter T-cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here, we review recent advances in our understanding of hyperlipidemia in graft rejection. Hyperlipidemic mice have significant increases in serum levels of proinflammatory cytokines, and neutralization of interleukin 17 (IL-17) slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T-cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3 T cells that led to reduced Treg function and the expansion of FoxP3 CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory-molecule blockade, a strategy that requires Tregs. These findings highlight the importance of considering the contribution of inflammatory comorbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population.

Characterization of age-associated exhausted CD8⁺ T cells defined by increased expression of Tim-3 and PD-1.

Aging is accompanied by altered T-cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T-cell exhaustion and aging-associated immune dysfunction. In this study, we demonstrate that T-cell immunoglobulin mucin domain-3 (Tim-3), another exhaustion marker, is up-regulated on aged T cells, especially CD8(+) T cells. Tim-3-expressing cells also produced PD-1, but Tim-3(+) PD-1(+) CD8(+) T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim-3(-) PD-1(+) cells. Tim-3(+) PD-1(+) CD8(+) T cells showed more evident properties associated with exhaustion than Tim-3(-) PD-1(+) CD8(+) T cells: an exhaustion-related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL-10 and induced normal CD8(+) T cells to produce IL-10, which might contribute to immune dysregulation in aged mice. The generation of Tim-3-expressing CD8(+) T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8(+) T-cell population with age-associated exhaustion was distinguishable by its expression of Tim-3. These results provide clues for understanding the alterations that occur in T-cell populations with age and for improving dysfunctions related to the aging of the immune system.

Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants.

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.

Lethal giant larvae‐1 deficiency enhances the CD8+ effector T‐cell response to antigen challenge in vivo

Lethal giant larvae-1 (Lgl-1) is an evolutionary conserved protein that regulates cell polarity in diverse lineages; however, the role of Lgl-1 in the polarity and function of immune cells remains to be elucidated. To assess the role of Lgl-1 in T cells, we generated chimeric mice with a hematopoietic system deficient for Lgl-1. Lgl-1 deficiency did not impair the activation or function of peripheral CD8(+) T cells in response to antigen presentation in vitro, but did skew effector and memory T-cell differentiation. When challenged with antigen-expressing virus or tumor, Lgl-1-deficient mice displayed altered T-cell responses. This manifested in a stronger antiviral and antitumor effector CD8(+) T-cell response, the latter resulting in enhanced control of MC38-OVA tumors. These results reveal a novel role for Lgl-1 in the regulation of virus-specific T-cell responses and antitumor immunity.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.

A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P=0·446) nor with cessation of leflunomide treatment due to side effects (P=0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.

Rhinoscleroma in a 5-year-old Portuguese Child

Rhinoscleroma is a chronic granulomatous infectious disease that is rare in Western Europe. We report the case of a 5-year-old Portuguese boy diagnosed with rhinoscleroma in the context of recurrent epistaxis. He had a 6-month course of antibiotic (amoxicillin plus clavulanate) therapy with full recovery.

Immune alterations induced by chronic noise exposure: Comparison with restraint stress in BALB/c and C57Bl/6 mice

Exposure to loud noise levels represents a problem in all regions of the world. Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra-auditory. In particular, it has been proposed that noise could affect immune system similarly to other stressors. Nevertheless, only a few studies so far have investigated the effects of noise on the immune function. The aim of the present work was to investigate the effect of chronic (2 weeks) noise (95–97 dBA) exposure on immune responses in BALB/c and C57 mice. To ascertain if the effect of noise is similar to other psychological stressors, the effect of chronic restraint—applied for the same time—on immune response was also analyzed. It was found that chronic noise impaired immune-related end-points in vivo and ex vivo depending on the strain used. Noise, but not restraint, affected C57Bl/6 mouse T-cell-dependent antibody production and ex vivo stimulated T-cell proliferation, but had no effect on these parameters in BALB/c mice or their cells. In fact, none of the stressors altered T-cell responses associated with the BALB/c mice. Further, noise exposure induced a decrease in corticosterone and catecholamines levels in BALB/c mice. In contrast, no differences were seen in these parameters for those BALB/c mice under restraint or for that matter C57Bl/6 mice exposed to restraint or noise. The results of these studies indicate that noise could seriously affect immune responses in susceptible individuals. In addition, it may also be concluded that noise possibility should not be considered a classic stressor.

Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis.

BackgroundAnti-viral CD8 T-cell activity is enhanced and prolonged by CD4 T-cell-mediated help, but negatively regulated by inhibitory B7-H1 interactions. During viral encephalomyelitis, the absence of CD4 T cells decreases CD8 T cell activity and impedes viral control in the central nervous system (CNS). By contrast, the absence of B7-H1 enhances CD8 T-cell function and accelerates viral control, but increases morbidity. However, the relative contribution of CD4 T cells to CD8 function in the CNS, in the absence of B7-H1, remains unclear.MethodsWild-type (WT) and B7-H1−/− mice were infected with a gliatropic coronavirus and CD4 T cells depleted to specifically block T helper function in the CNS. Flow cytometry and gene expression analysis of purified T-cell populations from lymph nodes and the CNS was used to directly monitor ex vivo T-cell effector function. The biological affects of altered T-cell responses were evaluated by analysis of viral control and spinal-cord pathology.ResultsIncreased anti-viral activity by CD8 T cells in the CNS of B7-H1−/− mice was lost upon depletion of CD4 T cells; however, despite concomitant loss of viral control, the clinical disease was less severe. CD4 depletion in B7-H1−/− mice also decreased inducible nitric oxide synthase expression by microglia and macrophages, consistent with decreased microglia/macrophage activation and reduced interferon (IFN)-γ. Enhanced production of IFN-γ, interleukin (IL)-10 and IL-21 mRNA was seen in CD4 T cells from infected B7-H1−/− compared with WT mice, suggesting that over-activated CD4 T cells primarily contribute to the increased pathology.ConclusionsThe local requirement of CD4 T-cell help for CD8 T-cell function is not overcome if B7-H1 inhibitory signals are lost. Moreover, the increased effector activity by CD8 T cells in the CNS of B7-H1−/− mice is attributable not only to the absence of B7-H1 upregulation on major histocompatibility complex class I-presenting resident target cells, but also to enhanced local CD4 T-cell function. B7-H1-mediated restraint of CD4 T-cell activity is thus crucial to dampen both CD8 T-cell function and microglia/macrophage activation, thereby providing protection from T-cell-mediated bystander damage.

Natural Transmission of Plasmodium berghei Exacerbates Chronic Tuberculosis in an Experimental Co-Infection Model

Human populations are rarely exposed to one pathogen alone. Particularly in high incidence regions such as sub-Saharan Africa, concurrent infections with more than one pathogen represent a widely underappreciated public health problem. Two of the world’s most notorious killers, malaria and tuberculosis, are co-endemic in impoverished populations in the tropics. However, interactions between both infections in a co-infected individual have not been studied in detail. Both pathogens have a major impact on the lung as the prime target organ for aerogenic Mycobacterium tuberculosis and the site for one of the main complications in severe malaria, malaria-associated acute respiratory distress syndrome (MA-ARDS). In order to study the ramifications caused by both infections within the same host we established an experimental mouse model of co-infection between Mycobacterium tuberculosis and Plasmodium berghei NK65, a recently described model for MA-ARDS. Our study provides evidence that malaria-induced immune responses impair host resistance to Mycobacterium tuberculosis. Using the natural routes of infection, we observed that co-infection exacerbated chronic tuberculosis while rendering mice less refractory to Plasmodium. Co-infected animals presented with enhanced inflammatory immune responses as reflected by exacerbated leukocyte infiltrates, tissue pathology and hypercytokinemia accompanied by altered T-cell responses. Our results - demonstrating striking changes in the immune regulation by co-infection with Plasmodium and Mycobacterium - are highly relevant for the medical management of both infections in humans.

A hypoallergenic variant of the major birch pollen allergen shows distinct characteristics in antigen processing and T‐cell activation

BM4 is a novel genetically engineered variant of the major birch pollen allergen Bet v 1 that lacks the typical Bet v 1-like fold and displays negligible IgE-binding but strong T cell-activating capacity. The aim of this study was to elucidate possible differences between BM4 and Bet v 1 in internalization, antigen processing, and presentation. Proliferative responses to BM4 and Bet v 1 of peripheral blood mononuclear cells and Bet v 1-specific T-cell clones were compared. Fluorescently labeled BM4 and Bet v 1 were used to study surface binding, endocytosis, and intracellular degradation by monocyte-derived DC (mdDC). Both proteins were digested by endolysosomal extracts of mdDC. BM4- and Bet v 1-pulsed mdDC were employed to assess the kinetics of activation of Bet v 1-specific T-cell clones and the polarization of naïve T cells. BM4 displayed a significantly stronger T cell-activating capacity than Bet v 1. Furthermore, BM4 showed increased surface binding and internalization as well as faster endolysosomal degradation compared with Bet v 1. BM4-pulsed mdDC induced enhanced proliferative responses at earlier time-points in Bet v 1-specific T-cell clones and promoted less IL-5 production in T cells than Bet v 1-pulsed mdDC. The loss of the Bet v 1-fold changes the protein's interaction with the human immune system at the level of antigen-presenting cells resulting in altered T-cell responses. By combining low IgE-binding with strong and modulating T cell-activating capacity, BM4 represents a highly interesting candidate for specific immunotherapy of birch pollen allergy.