Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm, Katharine V.; Thorpe, Jerill; Murray, Scott O.; Gavin, Marc A.; Speake, Cate; Greenbaum, Carla J.; Cerosaletti, Karen; Buckner, Jane H.; Long, S. Alice

doi:10.1016/j.clim.2017.06.004

Cited by 9 publications

(9 citation statements)

References 45 publications

(76 reference statements)

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“…The sum of knowledge generated regarding T1D pathogenesis through particular HLA-DR alleles binding to specific autoantigenic epitopes could lead to the design of antigenspecific interventions (perhaps coupled with nonspecific ones) either in the pre-or in the new-onset T1D phase. The targets would probably have to include effector as well as regulatory CD4/CD8 T cells (48)(49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

et al. 2019

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Next-generation targeted sequencing of HLA-DRB1 and HLA-DRB3, -DRB4, and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity as a result of high polymorphisms and extended linkage disequilibrium among the DR loci, we applied a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease-associated DR sequences and identifies 11 residues of DRB1, sequences of which retain all significant associations observed by DR genes. Furthermore, all 11 residues locate under/adjoining the peptide-binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. The 15 residues of DRB345, located respectively in the β49–55 homodimerization patch and on the face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds that DRB1 residues significantly associated with ZnT8A and DRB345 residues with GADA. The strongest association is between four residues (β14, β25, β71, and β73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15, P = 10 −18 ), and another sequence, ERKG, confers a protective association (odds ratio 0.59, P = 10 −11 ), despite a difference of only one amino acid. Because motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.

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Section: Discussionmentioning

confidence: 99%

Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

et al. 2019

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“…c Autoantigen-specific reactivities (41,42). c IL-2 signaling defect (55)(56)(57), Treg activity (reviewed in 58), CD8 antigen experience, and exhaustion (59) c Type I interferon signature: detected in peripheral whole blood and purified neutrophils (47)(48)(49). c Activation of innate immunity: detected in circulation (22,50).…”

Section: The Impact Of Type 1 Diabetes Heterogeneity On Clinical Triamentioning

confidence: 99%

Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes

et al. 2019

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The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.Describing aspects of biology as "heterogeneous" often has a negative connotation. It is a term that is used when we do not understand a measured or observed aspect of disease or when we need to explain data that are not consistent. However, it is evident that recognizing that there are "different kinds" of cells, genes, types of response, and severity of disease could offer a set of opportunities for therapies to work and biomarkers to be meaningful. Thus, it may be time to exploit heterogeneity rather than curse it and to use the opportunity to carve out endotypes of type 1 diabetes that have traction both in the clinic and in the laboratory.The introduction of the term "endotype" can largely be attributed to developments in the field of asthma (1) when it became apparent in the late 1990s that different pathogenic mechanisms induce a similar symptom cluster and manifest as a

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“…We and others have reported reduced IL-2 response in CD4 + CD45RO + memory T cells associated with T1D and T1Dassociated risk alleles (18,19,40,41). In this study, we assessed whether this phenotype precedes diagnosis in our risk-stratified cohort.…”

Section: Il-2 Response Is Decreased In Autoab + Subjects Prior To Disease Onsetmentioning

confidence: 96%

“…Tfh cells are also increased in autoantibody-positive (autoAb + ) children with impaired glucose tolerance, suggesting the evolution of a pathogenic Tfh population poised to promote B-cell responses during disease progression (15). Functional consequences likely underlie these phenotypes, as CD4 + Teffs are resistant to regulatory T-cell (Treg) suppression (16,17) and exhibit altered responses to cytokines, having a blunted response to interleukin (IL)-2 (18,19) and an enhanced response to IL-6 (20), in established T1D.…”

mentioning

confidence: 99%

Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression

Habib¹,

Long²,

Samuels³

et al. 2019

Diabetes

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Multiple studies of B-and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T-and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.

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Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Cited by 9 publications

References 45 publications

Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes

Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes

Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression

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