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We analyzed T cell subsets from cryopreserved PBMC obtained from the TrialNet Pathway to Prevention archives. We compared subjects who had previously seroconverted for one or more autoantibodies with non-seroconverted, autoantibody negative individuals. We observed a reduced frequency of MAIT cells among seroconverted subjects. Seroconverted subjec...
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Citations
... Seroconverted participants had decreased frequencies of mucosal associated invariant T cell (MAIT) and CD127 dim CD4 + regulatory T cells (Tregs) compared with islet antibody negative (Ab-) participants. An increased ratio of short-lived effector CD8 + T cells (SLEC) T cells to MAIT cells as well as SLEC : CD127 dim cells was found in all seroconverted individuals (progressors and non-progressors) compared with Ab-participants (20). The increase in SLEC was highest amongst seroconverted individuals that later progressed to T1D (20). ...
... An increased ratio of short-lived effector CD8 + T cells (SLEC) T cells to MAIT cells as well as SLEC : CD127 dim cells was found in all seroconverted individuals (progressors and non-progressors) compared with Ab-participants (20). The increase in SLEC was highest amongst seroconverted individuals that later progressed to T1D (20). The SLEC (CD127-, CD27-, CD57+, CD28-) phenotype indicates short-lived, terminally differentiated cells undergoing chronic stimulation with cytotoxic potential. ...
Aim:
Progression to type 1 diabetes (T1D) is defined in stages and clinical disease is preceded by a period of silent autoimmunity. Improved prediction of the risk and rate of progression to T1D is needed to reduce the prevalence of diabetic ketoacidosis at presentation as well as for staging participants for clinical trials. This systematic review evaluates novel circulating biomarkers associated with future progression to T1D.
Methods:
PubMed, Ovid, and EBSCO databases were used to identify a comprehensive list of articles. The eligibility criteria included observational studies that evaluated the usefulness of circulating markers in predicting T1D progression in at-risk subjects <20 years old.
Results:
Twenty-six studies were identified, seventeen were cohort studies and ten were case control studies. From the 26 studies, 5 found evidence for protein and lipid dysregulation, 11 identified molecular markers while 12 reported on changes in immune parameters during progression to T1D. An increased risk of T1D progression was associated with the presence of altered gene expression, immune markers including regulatory T cell dysfunction and higher short-lived effector CD8+ T cells in progressors.
Discussion:
Several circulating biomarkers are dysregulated before T1D diagnosis and may be useful in predicting either the risk or rate of progression to T1D. Further studies are required to validate these biomarkers and assess their predictive accuracy before translation into broader use.
Systematic review registration:
https://www.crd.york.ac.uk/prospero, identifier (CRD42020166830).
... Similarly, pre-existing CMV infection promoted the expansion of CD28 − CD8 + T cells during the progression of Type 1 Diabetes (T1D). The increased frequency of these CD28 − CD8 + T cells in T1D was also related to the death of pancreatic beta cells, thus reinforcing the contribution of such herpesvirus in switching the T compartment towards a senescent profile with consequences on the disease severity in genetically predisposed subjects [79]. ...
CD8+ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8+ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8+ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer.
... Recently, we completed an analysis of peripheral blood mononuclear cells examining T cell subsets for individuals at-risk for type 1 diabetes (19). Among several intriguing observations, we found a reduction in frequency of MAIT cells in firstand second-degree relatives of subjects diagnosed with T1D. ...
... Cells were then distributed to 96-well plates for surface staining. Surface staining was conducted as described previously (19). The following antibodies and reagents were ...
... The phenotypic identification of MAIT cells in peripheral blood and their stratification into CD8 and double-negative (DN) subsets was identical to what we reported previously (19). A representative gating strategy and data depiction is presented in Supplementary Figure 1. ...
Mucosal-associated invariant T (MAIT) cells have been implicated in various forms of autoimmunity, including type 1 diabetes (T1D). Here, we tested the hypothesis that CD8 and double negative (DN) MAIT cell frequencies were altered among diagnosed T1D subjects compared to controls. To do this, we analyzed cryopreserved peripheral blood mononuclear cells (PBMCs) from age-matched T1D and control children using flow cytometry. We observed that CD8 and DN MAIT cell frequencies were similarly abundant between the two groups. We tested for associations between MAIT cell frequency and T1D-associated parameters, which could reveal a pathogenic role for MAIT cells in the absence of changes in frequency. We found no significant associations between CD8 and DN MAIT cell frequency and levels of islet cell autoantibodies (ICA), glutamate decarboxylase 65 (GAD65) autoantibodies, zinc transporter 8 (ZNT8) autoantibodies, and insulinoma antigen 2 (IA-2) autoantibodies. Furthermore, CD8 and DN MAIT cell frequencies were not significantly associated with time since diagnosis, c-peptide levels, HbA1c, and BMI. As we have examined this cohort for multiple soluble factors previously, we tested for associations between relevant factors and MAIT cell frequency. These could help to explain the broad range of MAIT frequencies we observed and/or indicate disease-associated processes. Although we found nothing disease-specific, we observed that levels of IL-7, IL-18, 25 (OH) vitamin D, and the ratio of vitamin D binding protein to 25 (OH) vitamin D were all associated with MAIT cell frequency. Finally, previous cytomegalovirus infection was associated with reduced CD8 and DN MAIT cells. From this evaluation, we found no connections between CD8 and DN MAIT cells and children with T1D. However, we did observe several intrinsic and extrinsic factors that could influence peripheral MAIT cell abundance among all children. These factors may be worth consideration in future experimental design.
... A more recent study observed a markedly reduced frequency of circulating MAIT cells in patients with newly diagnosed type 1 diabetes [35]. One more study suggested that the frequency of circulating MAIT cells was also reduced in AAb + at-risk individuals [36]. Variable alterations in CD25, programmed cell death protein 1 (PD-1), C-C chemokine receptor type (CCR)6 and CD27 surface marker expression, as well as IFN-γ and IL-4 production, by peripheral blood MAIT cells from individuals with type 1 diabetes have also been reported in these studies [34,35]. ...
... MAIT ↔ [36] MAIT ↓ [35] CCR6 + MAIT ↓ [35] CD25 + MAIT ↑ [35] PD-1 + MAIT ↑ [35] IFN-γ + MAIT ↓ [35] 'MAIT-like' ↔ [34] MAIT ↔ [35] CD27 − 'MAIT-like' ↑ [34] IFN-γ + MAIT ↓ [35] a b Fig. 7 Peripheral blood MAIT cell alterations during the progression of type 1 diabetes (T1D). Alterations observed in our study in the paediatric cohort (a) and adult cohort (b) are displayed above the black line and those reported in previous studies [34][35][36] are listed below the black line. ...
... MAIT ↔ [36] MAIT ↓ [35] CCR6 + MAIT ↓ [35] CD25 + MAIT ↑ [35] PD-1 + MAIT ↑ [35] IFN-γ + MAIT ↓ [35] 'MAIT-like' ↔ [34] MAIT ↔ [35] CD27 − 'MAIT-like' ↑ [34] IFN-γ + MAIT ↓ [35] a b Fig. 7 Peripheral blood MAIT cell alterations during the progression of type 1 diabetes (T1D). Alterations observed in our study in the paediatric cohort (a) and adult cohort (b) are displayed above the black line and those reported in previous studies [34][35][36] are listed below the black line. E, established (more than 10 days after diagnosis); ND, newly diagnosed (less than 10 days after diagnosis); NP, non-progressor; P, progressor Of the MAIT cell alterations observed here, decreased expression of CD27 and production of IFN-γ have also been reported by others in patients with type 1 diabetes [34,35] (Fig. 7). ...
Aims/hypothesis
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise derivatives of bacterial riboflavin metabolites presented by MHC-Ib-related protein 1 (MR1) molecules and are important effector cells for mucosal immunity. Their development can be influenced by the intestinal microbiome. Since the development of type 1 diabetes has been associated with changes in the gut microbiome, this can be hypothesised to lead to alterations in circulating MAIT cells. Accordingly, peripheral blood MAIT cell alterations have been reported previously in patients with type 1 diabetes. However, a comprehensive analysis of the frequency and phenotype of circulating MAIT cells at different stages of type 1 diabetes progression is currently lacking.
Methods
We analysed the frequency, phenotype and functionality of peripheral blood MAIT cells, as well as γδ T cells, invariant natural killer T (iNKT) cells and natural killer (NK) cells with flow cytometry in a cross-sectional paediatric cohort (aged 2–15) consisting of 51 children with newly diagnosed type 1 diabetes, 27 autoantibody-positive (AAb⁺) at-risk children, and 113 healthy control children of similar age and HLA class II background. The frequency of MAIT cells was also assessed in a separate cross-sectional adult cohort (aged 19–39) of 33 adults with established type 1 diabetes and 37 healthy individuals of similar age.
Results
Children with newly diagnosed type 1 diabetes displayed a proportional increase of CD8⁻CD27⁻ MAIT cells compared with healthy control children (median 4.6% vs 3.1% of MAIT cells, respectively, p = 0.004), which was associated with reduced expression of C-C chemokine receptor (CCR)5 (median 90.0% vs 94.3% of MAIT cells, p = 0.02) and β7 integrin (median 73.5% vs 81.7% of MAIT cells, p = 0.004), as well as decreased production of IFN-γ (median 57.1% vs 69.3% of MAIT cells, p = 0.04) by the MAIT cells. The frequency of MAIT cells was also decreased in AAb⁺ children who later progressed to type 1 diabetes compared with healthy control children (median 0.44% vs 0.96% of CD3⁺ T cells, p = 0.04), as well as in adult patients with a short duration of type 1 diabetes (less than 6 years after diagnosis) compared with control individuals (median 0.87% vs 2.19% of CD3⁺ T cells, p = 0.007). No alterations in γδ T cell, iNKT cell or NK cell frequencies were observed in children with type 1 diabetes or in AAb⁺ children, with the exception of an increased frequency of IL-17A⁺ γδ T cells in children with newly diagnosed diabetes compared with healthy control children (median 1.58% vs 1.09% of γδ T cells, p = 0.002).
Conclusions/interpretation
Changes in the frequency and phenotype of circulating MAIT cells were detectable before, at the onset and after diagnosis of type 1 diabetes in cross-sectional cohorts. Our results suggest a possible temporal association between peripheral blood MAIT cell alterations and the clinical onset of type 1 diabetes.
Graphical abstract
... The latter studies employed the same 32-parameter mass cytometry-staining panel, incorporated functional immune cell profiling (PMA/ionomycin-induced IFNg and IL-4/10/17A production), and even included samples from donors with other autoimmune endocrine disorders (Hashimoto's thyroiditis, Grave's disease, Addison's disease [27]) to effectively harness the discovery potential of mass cytometry analyses. Yet the relevance of the reported results, not least on account of the small study cohort size, is difficult to ascertain because of challenges to relate particular immune subset alterations to other and at times seemingly contrasting observations (what to make, for example, of the increased preponderance of different natural killer (NK) cell subsets in at-risk children and new onset T1D cases [26,27] vs. a reduction of total and various natural killer cell subsets previously reported for new onset T1D cases in ref. [28] and several other studies; or the elevated vs. reduced frequencies of different CD4 þ T REG subsets in at-risk individuals that only share a CD127 À CCR4 þ CCR7 À backbone [26,29]; or the decrease of a CD8 þ T EMRA subpopula- [27] vs. elevated numbers of CD8 þ T SLEC (short-lived effector-like cells) defined by a CD57 þ CD27 À CD28 À CD127 À phenotype in seroconverted subjects [29]). The preceding discussion, including its cumbersome references to complex cellular phenotypes, also highlights a terminological conundrum exacerbated by the very potential of high-dimensional immune cell sub-setting, namely the continued use of descriptive short-hand definitions that equate limited phenotypic properties with cellular differentiation states and functional properties [e.g. ...
... The latter studies employed the same 32-parameter mass cytometry-staining panel, incorporated functional immune cell profiling (PMA/ionomycin-induced IFNg and IL-4/10/17A production), and even included samples from donors with other autoimmune endocrine disorders (Hashimoto's thyroiditis, Grave's disease, Addison's disease [27]) to effectively harness the discovery potential of mass cytometry analyses. Yet the relevance of the reported results, not least on account of the small study cohort size, is difficult to ascertain because of challenges to relate particular immune subset alterations to other and at times seemingly contrasting observations (what to make, for example, of the increased preponderance of different natural killer (NK) cell subsets in at-risk children and new onset T1D cases [26,27] vs. a reduction of total and various natural killer cell subsets previously reported for new onset T1D cases in ref. [28] and several other studies; or the elevated vs. reduced frequencies of different CD4 þ T REG subsets in at-risk individuals that only share a CD127 À CCR4 þ CCR7 À backbone [26,29]; or the decrease of a CD8 þ T EMRA subpopula- [27] vs. elevated numbers of CD8 þ T SLEC (short-lived effector-like cells) defined by a CD57 þ CD27 À CD28 À CD127 À phenotype in seroconverted subjects [29]). The preceding discussion, including its cumbersome references to complex cellular phenotypes, also highlights a terminological conundrum exacerbated by the very potential of high-dimensional immune cell sub-setting, namely the continued use of descriptive short-hand definitions that equate limited phenotypic properties with cellular differentiation states and functional properties [e.g. ...
Purpose of review:
New single-cell tec. hnologies developed over the past decade have considerably reshaped the biomedical research landscape, and more recently have found their way into studies probing the pathogenesis of type 1 diabetes (T1D). In this context, the emergence of mass cytometry in 2009 revolutionized immunological research in two fundamental ways that also affect the T1D world: first, its ready embrace by the community and rapid dissemination across academic and private science centers alike established a new standard of analytical complexity for the high-dimensional proteomic stratification of single-cell populations; and second, the somewhat unexpected arrival of mass cytometry awoke the flow cytometry field from its seeming sleeping beauty stupor and precipitated substantial technological advances that by now approach a degree of analytical dimensionality comparable to mass cytometry.
Recent findings:
Here, we summarize in detail how mass cytometry has thus far been harnessed for the pursuit of discovery studies in T1D science; we provide a succinct overview of other single-cell analysis platforms that already have been or soon will be integrated into various T1D investigations; and we briefly consider how effective adoption of these technologies requires an adjusted model for expense allocation, prioritization of experimental questions, division of labor, and recognition of scientific contributions.
Summary:
The introduction of contemporary single-cell technologies in general, and of mass cytometry, in particular, provides important new opportunities for current and future T1D research; the necessary reconfiguration of research strategies to accommodate implementation of these technologies, however, may both broaden research endeavors by fostering genuine team science, and constrain their actual practice because of the need for considerable investments into infrastructure and technical expertise.
... Studies have indicated that proinflammatory cells such as Th1, Th17, and CTL, which increase in obesity and diabetes, also modulate insulin signaling (3,6). Conversely, a number of antiinflammatory cells, such as Th2 and regulatory T cell (Treg), have been associated with the protection of insulin sensitivity (7). ...
Mucosal-associated invariant T (MAIT) cells play a key role in local and systemic immune responses. Studies suggest that type 2 diabetes (T2D) is associated with alterations in the human MAIT cell response. However, the mechanisms that regulate the survival and homeostasis of human MAIT cells are poorly defined. In this study, we demonstrate that the costimulatory TNF superfamily receptor OX40 was highly expressed in MAIT cells of patients with T2D. Compared with OX40-negative MAIT cells, OX40-positive MAIT cells showed a high activation and a memory phenotype. Surprisingly, OX40 expression was negatively correlated with the frequency of MAIT cells in the peripheral blood of T2D patients. Increased cleaved caspase-3 levels were observed in OX40+-expressing MAIT cells in T2D patients. In vitro, activated OX40 signaling by recombinant OX40L protein promoted caspase-3 activation and apoptosis of MAIT cells. Inhibition of caspase-3 restored apoptosis of MAIT cells induced by OX40 signaling. These results identify OX40 as an amplifier of activation-induced cell death of human blood MAIT cells and shed new light on the regulation of MAIT cells in the phase of immune responses in T2D.
... In addition, recent studies suggest that alterations in circulating CD4+ and CD8+ T cell compartments precede RA onset [41*,42*]. Of interest, early RA patients have elevated Th1 cells [43], and preclinical RA involves an imbalance of effector T cell subsets with regulatory T cells (Tregs) along with dysfunctional inhibitory pathways, such as PD-1 [43][44][45][46]. B cells are also altered in pre-clinical RA. ...
Progression from health to a classified autoimmune disease is an evolving process that can happen rapidly in some diseases, but usually takes years to develop. Specific immune alterations predate pathogenic autoimmunity and can be used as disease biomarkers to identify high-risk individuals for prevention studies applied in the pre-clinical state. Here we discuss recent findings that illuminate specific immune pathways that are altered in the earliest phases of pre-clinical autoimmunity as well as those mediators more closely associated with later clinically apparent and classified disease onset.
... A reduced number of MAIT cells (CD3 + CD4 -CD8 + CD161 + TRAV1-2 + or CD3 + CD4 -CD8 − CD161 + TRAV1-2 + ) has been detected in the blood of children with type 1 diabetes (T1D), relative to the number in healthy subjects, but not before disease onset, as assessed in a small cohort of seroconverted at-risk subjects who expressed anti-islet antibodies 128 . Conversely, a different team reported fewer MAIT cells in seroconverted at-risk subjects than in healthy control subjects 129 but not in children who progressed to T1D 129,130 . MAIT cells in patients with recent-onset T1D produced less IFN-γ, more TNF and slightly more IL-4 and IL-17A than did those from healthy control subjects 128 , although other non-MAIT cells in the MAIT celldiminished CD161 + TRAV1-2 + population might have contributed to some of these effects. ...
... A reduced number of MAIT cells (CD3 + CD4 -CD8 + CD161 + TRAV1-2 + or CD3 + CD4 -CD8 − CD161 + TRAV1-2 + ) has been detected in the blood of children with type 1 diabetes (T1D), relative to the number in healthy subjects, but not before disease onset, as assessed in a small cohort of seroconverted at-risk subjects who expressed anti-islet antibodies 128 . Conversely, a different team reported fewer MAIT cells in seroconverted at-risk subjects than in healthy control subjects 129 but not in children who progressed to T1D 129,130 . MAIT cells in patients with recent-onset T1D produced less IFN-γ, more TNF and slightly more IL-4 and IL-17A than did those from healthy control subjects 128 , although other non-MAIT cells in the MAIT celldiminished CD161 + TRAV1-2 + population might have contributed to some of these effects. ...
... MAIT cells in blood121,215 ; residual MAIT cells ↓ IFN-γ, ↑ PD-1 121 , ↑ CD69 215 MAIT cells in blood ↓ 129 or not 128 in pre-diabetic sero-converted subjects; MAIT cells in blood ↓ 128 or not129,130 in patients with T1D; residual MAIT cells activated ↑ CD25, PD-1, TNF, IL-4, IL-17, GzB, ↓ IFNγ 128 ; no MAIT cells detected in insulitic lesions of newly diagnosed patients 131 MAIT cells in blood; residual MAIT cells activated 116-118 ; ↑IL-17 116-118 ; ↑IL-22 115,117 ; MAIT cells ↑ 116-118 or ↓ 115 in inflamed mucosa 115-118 CAIA, collagen-antibody-induced arthritis; CIA, collagen-induced arthritis; COPD, chronic obstructive pulmonary disease; PBC, primary biliary cholangitis; SLE, systemic lupus erythematosus. ...
In recent years, a population of unconventional T cells called 'mucosal-associated invariant T cells' (MAIT cells) has captured the attention of immunologists and clinicians due to their abundance in humans, their involvement in a broad range of infectious and non-infectious diseases and their unusual specificity for microbial riboflavin-derivative antigens presented by the major histocompatibility complex (MHC) class I-like protein MR1. MAIT cells use a limited T cell antigen receptor (TCR) repertoire with public antigen specificities that are conserved across species. They can be activated by TCR-dependent and TCR-independent mechanisms and exhibit rapid, innate-like effector responses. Here we review evidence showing that MAIT cells are a key component of the immune system and discuss their basic biology, development, role in disease and immunotherapeutic potential.
