ABSTRACT
The cross-talk between the innate and adaptive immune response represents the first defense weapon against the threat of pathogens. Substantial evidence has shown a relationship between immune phenotype lymphocytes and COVID-19 disease severity and/or implication in susceptibility to SARS-CoV-2 infection. Recently, belonging to ABO blood groups has been investigated as a correlation factor to COVID-19 disease. This pilot study investigated lymphocyte typing in a cohort of blood donors to understand the underlying mechanism in SARS-CoV-2 infection linked to the blood group. The study cohort consisted of 20-64-year-old subjects, without comorbidities, from both sexes, who were COVID-19 vaccinated with previous or no infection history. Whole blood samples, collected at A.O.R.N. Sant'Anna and San Sebastiano Hospital (Campania Region), were processed by multiparametric cytofluorimetric assay, to characterize CD4+ helper and CD8+ cytotoxic T cell CD3+ subpopulations. The CD45RA, CCR7, CD27, CD28, CD57 and PD-1 markers were investigated to delineate the peripheral T-cell maturation stages. Differences were detected in ABO blood types in CD3+, CD4+ gated on CD3+, CD8+ and CD8+ gated on CD3+ percentage. These results contribute to identifying a memory cell "identikit" profile in COVID-19 disease, thus leading to a useful tool in precision medicine.
ABSTRACT
The mechanism involved in major depressive disorder (MDD) is well-studied but the mechanistic origin of the heterogeneous antidepressant effect remains largely unknown. Single-cell RNA-sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on peripheral blood mononuclear cells from 8 healthy individuals and 8 MDD patients before or after 12 weeks of antidepressant treatment is performed. scRNA-seq analysis reveals a lower proportion of naive T cells, particularly CD4+ naive T cells, in MDD patients compared to controls, and in nonresponders versus responders at the baseline. Flow cytometry data analysis of an independent cohort of 35 patients and 40 healthy individuals confirms the findings. Enrichment analysis of differentially expressed genes indicated obvious immune activation in responders. A specific activated CD4+ naive T population in responders characterized by enhanced mitogen-activated protein kinases (MAPK) pathway is identified. E-twenty six (ETS) is proposed as an upstream regulator of the MAPK pathway and heterogeneous differentiation in activated CD4+ naive T population is associated with the response to antidepressant treatment in MDD patients. A distinct immune feature manifested by CD4+ naive T cells during antidepressant treatment in MDD is identified. Collectively, this proposes the molecular mechanism that underlies the heterogeneous antidepressant outcomes for MDD.
Subject(s)
Antidepressive Agents , CD4-Positive T-Lymphocytes , Depressive Disorder, Major , Single-Cell Analysis , Humans , Depressive Disorder, Major/genetics , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/immunology , Male , Antidepressive Agents/therapeutic use , Antidepressive Agents/pharmacology , Female , Adult , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/drug effects , Middle Aged , Single-Cell Analysis/methods , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/metabolism , Cell Differentiation/drug effects , Cell Differentiation/genetics , RNA-Seq/methods , Sequence Analysis, RNA/methods , Single-Cell Gene Expression AnalysisABSTRACT
Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+ TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.
Subject(s)
Basic-Leucine Zipper Transcription Factors , CD4-Positive T-Lymphocytes , Cholangitis, Sclerosing , MicroRNAs , Polymorphism, Single Nucleotide , Humans , Cholangitis, Sclerosing/genetics , Cholangitis, Sclerosing/pathology , Cholangitis, Sclerosing/immunology , MicroRNAs/genetics , MicroRNAs/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Male , Polymorphism, Single Nucleotide/genetics , Female , Genetic Predisposition to Disease , Adult , Middle AgedABSTRACT
3' untranslated regions (3' UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBPs) and microRNAs that affect various aspects of the RNA life cycle including transcript stability and cellular localization. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3' UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3'-UTR dynamics in T helper cells, we investigated division-dependent alternative polyadenylation (APA). In addition, we generated 3' end UTR sequencing data from naive, activated, memory, and regulatory CD4+ T cells. 3'-UTR length changes were estimated using a nonnegative matrix factorization approach and were compared with those inferred from long-read PacBio sequencing. We found that APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNA-seq data set, we did not find evidence of APA association with differential gene expression or transcript usage, indicating that APA has only a marginal effect on transcript abundance. 3'-UTR sequence analysis revealed conserved binding sites for T cell-relevant microRNAs and RBPs in the alternative 3' UTRs. These results indicate that poly(A) site usage could play an important role in the control of cell fate decisions and homeostasis.
Subject(s)
MicroRNAs , Polyadenylation , 3' Untranslated Regions , MicroRNAs/genetics , MicroRNAs/metabolism , RNA-Seq , RNA, Messenger/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T-cell development and homeostasis is unknown. Using CD4cre -Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T-cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+ CD45.2+ ) and Trappc1 cKO naive T cells (CD45.2+ ) to CD45.1+ syngeneic mice, Trappc1-deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA-seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+ , Atf4-CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis-related damage-associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL-6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T-cell homeostasis to avoid proinflammatory naive T-cell death-caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T-cell biology.
Subject(s)
Ferroptosis , Hereditary Autoinflammatory Diseases , Mice , Animals , T-Lymphocytes , Mice, Knockout , Cell DifferentiationABSTRACT
The clinical expression of 22q11.2 deletion syndrome (22q11.2 DS) is extremely variable, as patients can present with recurrent or severe infections, immune dysregulation, atopic diseases, or extra-immunological manifestations. The immunological background underlying the different disease manifestations is not completely elucidated. The aim of this study was to identify the immunophenotypic peculiarities of 22q11.2 DS patients presenting with different disease expressions. This study included 34 patients with 22q11.2 DS, divided into three groups according to the clinical phenotype: isolated extra-immunological manifestations (G1), infectious phenotype with increased/severe infections (G2), and immune dysregulation (G3). The patients underwent extended immunophenotyping of the T and B lymphocytes and analysis of the circulating dendritic cells (DCs). In patients with an infectious phenotype, a significant reduction in CD3+ and CD4+ cells and an expansion of CD8 naïve cells was evidenced. On the other hand, the immunophenotype of the patients with immune dysregulation showed a skewing toward memory T cell populations, and reduced levels of recent thymic emigrants (RTEs), while the highest levels of RTEs were detected in the patients with isolated extra-immunological manifestations. This study integrates the current literature, contributing to elucidating the variability in the immune status of patients with 22q11.2DS with different phenotypic expressions, particularly in those with infectious phenotype and immune dysregulation.
ABSTRACT
Introduction: The lymphatic system has a pivotal role in immune homeostasis. To better understand this, we investigated the impact of Primary Lymphatic Anomalies (PLA) on lymphocyte numbers and phenotype. Methods: The study comprised (i) a retrospective cohort: 177 PLA subjects from the National Primary Lymphatic Anomaly Register with clinical and laboratory data, and (ii) a prospective cohort: 28 patients with PLA and 20 healthy controls. Patients were subdivided using established phenotypic diagnostic categories and grouped into simplex (localised tissue involvement only) and systemic (involvement of central lymphatics). Further grouping variables included genital involvement and the likelihood of co-existent intestinal lymphangiectasia. Haematology laboratory parameters were analysed in both cohorts. In the prospective cohort, prospective blood samples were analysed by flow cytometry for markers of proliferation, differentiation, activation, skin-homing, and for regulatory (CD4+Foxp3+) T cells (Treg). Results: In patients with PLA, lymphopaenia was frequent (22% of subjects), affected primarily the CD4+ T cell subset, and was more severe in subjects with systemic versus simplex patterns of disease (36% vs 9% for lymphopaenia; 70% vs 33% for CD4+ cells). B cells, NK cells and monocytes were better conserved (except in GATA2 deficiency characterised by monocytopaenia). Genital oedema and likelihood of concomitant intestinal lymphangiectasia independently predicted CD4+ T cell depletion. Analysing CD4+ and CD8+ T cells by differentiation markers revealed disproportionate depletion of naïve cells, with a skewing towards a more differentiated effector profile. Systemic PLA conditions were associated with: increased expression of Ki67, indicative of recent cell division, in naïve CD4+, but not CD8+ T cells; increased levels of activation in CD4+, but not CD8+ T cells; and an increased proportion of Treg. Skin-homing marker (CCR10, CLA and CCR4) expression was reduced in some patients with simplex phenotypes. Discussion: Patients with PLA who have dysfunctional lymphatics have a selective reduction in circulating lymphocytes which preferentially depletes naïve CD4+ T cells. The presence of systemic disease, genital oedema, and intestinal lymphangiectasia independently predict CD4 lymphopaenia. The association of this depletion with immune activation and increased circulating Tregs suggests lymphatic-lymphocyte interactions and local inflammatory changes are pivotal in driving immunopathology.
Subject(s)
Antigens, Differentiation, T-Lymphocyte , CD8-Positive T-Lymphocytes , Humans , Retrospective Studies , Prospective Studies , Antigens, Differentiation, T-Lymphocyte/metabolism , Edema , PolyestersABSTRACT
RATIONALE: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome. OBJECTIVES: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome. METHODS: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro. MEASUREMENTS AND MAIN RESULTS: We observed significant differences between patients and HCs in several T cell populations, including CD8+ and CD4+ T cells, Th1/Th17 subsets, CD4+ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4+ T cells and increased frequencies of Tregs and CD8+ γδ T cells correlated with worse outcome. Naïve CD4+ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs. CONCLUSIONS: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.
ABSTRACT
It is well-known that the functioning of the immune system gradually deteriorates with age, and we are increasingly confronted with its consequences as the life expectancy of the human population increases. Changes in the T-cell pool are among the most prominent features of the changing immune system during healthy ageing, and changes in the naive T-cell pool in particular are generally held responsible for its gradual deterioration. These changes in the naive T-cell pool are thought to be due to involution of the thymus. It is commonly believed that the gradual loss of thymic output induces compensatory mechanisms to maintain the number of naive T cells at a relatively constant level, and induces a loss of diversity in the T-cell repertoire. Here we review the studies that support or challenge this widely-held view of immune ageing and discuss the implications for vaccination strategies.
Subject(s)
Healthy Aging , T-Lymphocytes , Humans , Aging , Thymus GlandABSTRACT
The dynamics of cell populations are frequently studied in vivo using pulse-chase DNA labeling techniques. When combined with mathematical models, the kinetic of label uptake and loss within a population of interest then allows one to estimate rates of cell production and turnover through death or onward differentiation. Here we explore an alternative method of quantifying cellular dynamics, using a cell fate-mapping mouse model in which dividing cells can be induced to constitutively express a fluorescent protein, using a Ki67 reporter construct. We use a pulse-chase approach with this reporter mouse system to measure the lifespans and division rates of naive CD4 and CD8 T cells using a variety of modeling approaches, and show that they are all consistent with estimates derived from other published methods. However we propose that to obtain unbiased parameter estimates and full measures of their uncertainty one should simultaneously model the timecourses of the frequencies of labeled cells within both the population of interest and its precursor. We conclude that Ki67 reporter mice provide a promising system for modeling cellular dynamics.
Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Animals , Mice , Ki-67 Antigen , Models, Theoretical , Cell DifferentiationABSTRACT
OBJECTIVES: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). METHODS: We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. RESULTS: Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk.
Subject(s)
Diabetes Mellitus, Type 2 , Prediabetic State , Humans , Aged , Prediabetic State/epidemiology , Retirement , Interleukin-6 , Cross-Sectional Studies , T-Lymphocyte Subsets , Aging , Inflammation/epidemiologyABSTRACT
Naïve T cells and regulatory T cells, when purified, do not proliferate to the γc-cytokines IL-2, IL-7, or IL-15, despite their expression of cognate cytokine receptors. Dendritic cells (DCs) enabled the T cell proliferation to these cytokines, through cell-to-cell contact, but independent of T cell receptor stimulation. This effect lasted after separation of T cells from DCs, enabling enhanced proliferation of the T cells in DC-depleted hosts. We propose calling this a "preconditioning effect". Interestingly, IL-2 alone was sufficient to induce phosphorylation and nuclear translocation of STAT5 in T cells, but could not activate MAPK and AKT pathways and failed to induce transcription of IL-2 target genes. "Preconditioning" was necessary to activate these two pathways and induced weak Ca2+ mobilization independent of calcium release-activated channels. When preconditioning was combined with IL-2, full activation of downstream mTOR, 4E-BP1 hyperphosphorylation, and prolonged S6 phosphorylation occurred. Collectively, accessory cells provide T cell preconditioning, a unique activation mechanism, controlling cytokine-mediated proliferation of T cells.
Subject(s)
Cytokines , Interleukin Receptor Common gamma Subunit , Cytokines/metabolism , T-Lymphocytes, Regulatory/metabolism , Interleukin-2/pharmacology , Interleukin-2/metabolism , Dendritic Cells/metabolism , Cell ProliferationABSTRACT
Naive CD4+ T cells are more resistant to age-related loss than naive CD8+ T cells, suggesting mechanisms that preferentially protect naive CD4+ T cells during aging. Here, we show that TRIB2 is more abundant in naive CD4+ than CD8+ T cells and counteracts quiescence exit by suppressing AKT activation. TRIB2 deficiency increases AKT activity and accelerates proliferation and differentiation in response to interleukin-7 (IL-7) in humans and during lymphopenia in mice. TRIB2 transcription is controlled by the lineage-determining transcription factors ThPOK and RUNX3. Ablation of Zbtb7b (encoding ThPOK) and Cbfb (obligatory RUNT cofactor) attenuates the difference in lymphopenia-induced proliferation between naive CD4+ and CD8+ cells. In older adults, ThPOK and TRIB2 expression wanes in naive CD4+ T cells, causing loss of naivety. These findings assign TRIB2 a key role in regulating T cell homeostasis and provide a model to explain the lesser resilience of CD8+ T cells to undergo changes with age.
Subject(s)
CD8-Positive T-Lymphocytes , Lymphopenia , Aged , Animals , Humans , Mice , Aging , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Homeostasis , Proto-Oncogene Proteins c-akt/metabolism , Transcription Factors/metabolismABSTRACT
Acquired aplastic anemia (AA) is recognized as an immune-mediated disorder resulting from active destruction of hematopoietic cells in bone marrow (BM) by effector T lymphocytes. Bulk genomic landscape analysis and transcriptomic profiling have contributed to a better understanding of the recurrent cytogenetic abnormalities and immunologic cues associated with the onset of hematopoietic destruction. However, the functional mechanistic determinants underlying the complexity of heterogeneous T lymphocyte populations as well as their correlation with clinical outcomes remain to be elucidated. To uncover dysfunctional mechanisms acting within the heterogeneous marrow-infiltrating immune environment and examine their pathogenic interplay with the hematopoietic stem/progenitor pool, we exploited single-cell mass cytometry for BM mononuclear cells of severe AA (SAA) patients pre- and post-immunosuppressive therapy, in contrast to those of healthy donors. Alignment of BM cellular composition with hematopoietic developmental trajectories revealed potential functional roles for non-canonically activated CD4+ naïve T cells in newly-diagnosed pediatric cases of SAA. Furthermore, single-cell transcriptomic profiling highlighted a population of Th17-polarized CD4+CAMK4+ naïve T cells showing activation of the IL-6/JAK3/STAT3 pathway, while gene signature dissection indicated a predisposition to proinflammatory pathogenesis. Retrospective validation from our SAA cohort of 231 patients revealed high plasma levels of IL-6 as an independent risk factor of delayed hematopoietic response to antithymocyte globulin-based immunosuppressive therapy. Thus, IL-6 warrants further investigation as a putative therapeutic target in SAA.
Subject(s)
Anemia, Aplastic , Humans , Child , Anemia, Aplastic/genetics , Anemia, Aplastic/pathology , Interleukin-6/genetics , Retrospective Studies , Th17 Cells , Single-Cell Analysis , Janus Kinase 3 , STAT3 Transcription Factor/geneticsABSTRACT
This multiplex staining panel was developed to differentiate cattle T cells into conventional (CD4 and CD8) and unconventional (γδ-TCR) subsets as well as their stage of differentiation and activation. The combination of CD45RO and CD62L allows the identification of naïve (TNaïve ), central memory (TCM ), effector memory (TEM ) and terminal effector (TTE ) T cells. Activated cattle T cells (TAV ) can be identified by the cell surface expression of CD25. This panel was developed using cryopreserved cattle peripheral blood mononuclear cells (PBMCs) and tested on fresh as well as stimulated PBMCs. Therefore, this 8-color, 10-parameter flow cytometry panel simultaneously identifies cattle TNaïve , TAV , TCM , TEM , TTE and γδ-TCR cells. This panel will improve our ability to examine T-cell response to pathogens and vaccines in cattle including the potential to identify previously undescribed subpopulations. Furthermore, this panel can be readily optimized for other bovid species as many of these reagents are likely to cross react.
Subject(s)
Leukocytes, Mononuclear , T-Lymphocytes , Cattle , Animals , Leukocytes, Mononuclear/metabolism , Leukocyte Common Antigens/metabolism , Flow Cytometry , Receptors, Antigen, T-Cell , T-Lymphocyte Subsets , Immunologic Memory , CD4-Positive T-LymphocytesABSTRACT
BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation. OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function. RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients. CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκB's pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.
Subject(s)
Autoimmune Diseases , Transcription Factor RelB , Humans , Transcription Factor RelB/genetics , Transcription Factor RelB/metabolism , NF-kappa B/metabolism , Signal Transduction , Gene Expression Regulation , Autoimmune Diseases/geneticsABSTRACT
Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.
Subject(s)
COVID-19 , Humans , Adult , SARS-CoV-2 , CD4-Positive T-Lymphocytes , Immunity, Cellular , Lymphocyte Activation , Antibodies, ViralABSTRACT
A breakdown in cellular homeostasis is thought to drive naïve T cell aging, however the link between naïve T cell homeostasis and aging in humans is poorly understood. To better address this, we developed a lymphoid organoid system that maintains resting naïve T cells for more than 2 weeks, in conjunction with high CD45RA expression. Deep phenotypic characterization of naïve T cells across age identified reduced CD45RA density as a hallmark of aging. A conversion from CD45RAhigh naive cells to a CD45RAlow phenotype was reproduced within our organoid system by structural breakdown, but not by stromal cell aging or reduced lymphocyte density, and mediated by alternative CD45 splicing. Together, these data suggest that external influences within the lymph node microenvironment may cause phenotypic conversion of naïve T cells in older adults.
ABSTRACT
Mathematical models encoding biological hypotheses reveal new insight into the dynamics of naive immune cells in mice from birth to old age.
Subject(s)
Models, Theoretical , T-Lymphocytes , Animals , Mice , Models, BiologicalABSTRACT
The outcome of allogeneic hematopoietic cell transplantation (allo-HCT) largely depends on the development and management of graft-versus-host disease (GvHD), infections, and the occurrence of relapse of malignancies. Recent studies showed a lower incidence of chronic GvHD and severe acute GvHD in patients receiving naive T cell depleted grafts compared to patients receiving complete T cell depleted grafts. On the other hand, the incidence of acute GvHD in patients receiving cord blood grafts containing only naive T cells is rather low, while potent graft-versus-leukemia (GvL) responses have been observed. These data suggest the significance of naive T cells as both drivers and regulators of allogeneic reactions. The naive T cell pool was previously thought to be a quiescent, homogenous pool of antigen-inexperienced cells. However, recent studies showed important differences in phenotype, differentiation status, location, and function within the naive T cell population. Therefore, the adequate recovery of these seemingly innocent T cells might be relevant in the imminent allogeneic reactions after allo-HCT. Here, an extensive review on naive T cells and their contribution to the development of GvHD and GvL responses after allo-HCT is provided. In addition, strategies specifically directed to stimulate adequate reconstitution of naive T cells while reducing the risk of GvHD are discussed. A better understanding of the relation between naive T cells and alloreactivity after allo-HCT could provide opportunities to improve GvHD prevention, while maintaining GvL effects to lower relapse risk.