Pathophysiological characteristics of preproinsulin-specific CD8+ T cells in subjects with juvenile-onset and adult-onset type 1 diabetes: A 1-year follow-up study

Paul, Mahinder; Badal, Darshan; Jacob, Neenu; Dayal, Devi; Kumar, Rakesh; Bhansali, Anil; Bhadada, Sanjay Kumar; Sachdeva, Naresh

doi:10.1111/pedi.12536

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…Two other phenotypes we identified were unique to islet-specific cells (clusters 11 and 12) and not dominant among insulin-and virus-specific cells, indicating a different fate and function associated with exposure to native autoantigens from the pancreas as opposed to those seen for repeated viral antigen or abundant exogenous autoantigen as with insulin administra- tion. These findings confirm and expand reports by other groups which have shown in a more focused manner that not all isletspecific cells exhibit the same differentiation state (19,24,27,30,31,35,(43)(44)(45) and that the phenotype of islet-specific cells partially overlaps with chronic virus-specific cells (24,30,43,45).…”

Section: Discussionsupporting

confidence: 92%

“…Ample evidence indicates that islet-specific CD8 + T cells are a significant driver of β cell destruction in T1D (34). However, across numerous studies involving individuals with T1D, the frequencies of islet-specific CD8 + T cells in peripheral blood have been neither consistently altered nor strongly correlated with disease progression (11)(12)(13)(14)(15)35). Here, through an unbiased and multidimensional approach, we demonstrate that islet-specific CD8 + T cells of HCs and T1D subjects comprise 3 dominant phenotypes that display characteristics of transitional memory or exhausted memory cells.…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Wiedeman

Muir²,

Rosasco³

et al. 2019

Journal of Clinical Investigation

124

109

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 75%

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Wiedeman

Muir²,

Rosasco³

et al. 2019

Journal of Clinical Investigation

124

109

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“…Therefore, it appears that the age of onset has hardly any impact on the phenotype of peripheral PI‐specific Tregs in T1D. Our study, along with our previous reports, also proved that persistence of residual beta cell mass in AOT1D subjects could be attributed more to the propensity of anti‐beta cell T cell responses rather than antigen‐specific Tregs.…”

Section: Discussionsupporting

confidence: 77%

“…Thereby, subjects with AOT1D exhibit better preservation of beta cells mass . Owing to these factors, there are differences in the rate of antigen presentation and phenotype of T cell responses in JOT1D and AOT1D even with the same duration of disease . Whether the Treg compartment contributes to the preservation of beta cell mass in adult or late‐onset T1D is not yet known.…”

Section: Introductionmentioning

confidence: 99%

Characterization of proinsulin‐specific regulatory T cells in type 1 diabetes at different ages of onset

et al. 2019

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Background and Objectives Regulatory T cells (Tregs) play an important role in maintaining tolerance to self‐antigens. Defects in the frequency and function of polyclonal Tregs have been reported in type 1 diabetes (T1D). However, characteristics of proinsulin (PI)‐specific Tregs in human T1D have not yet been explored. Therefore, we aimed to characterize PI‐specific Tregs in two distinct pathophysiological subtypes of T1D, juvenile‐onset T1D (JOT1D) and adult‐onset T1D (AOT1D), distinguished by the age of onset. Methods Peripheral blood mononuclear cells of the recruited subjects were stimulated in vitro with PI‐derived peptides. PI‐specific Tregs were characterized by flow cytometry using the combination of markers CD25, CD137, FOXP3 and CD45RA. Results Firstly, we observed similar frequencies of polyclonal Tregs in the T1D (n = 25) and healthy control (HC) (n = 20) subjects (P = 0.96), with a positive correlation between age and frequency of polyclonal Tregs (r = +0.35, P = 0.04). While the frequency of polyclonal Tregs was higher in AOT1D group (P = 0.02), both JOT1D (n = 14) and AOT1D groups (n = 11) had a comparable frequency of PI‐specific Tregs in their peripheral blood. The frequency of PI‐specific memory Tregs was significantly high in both the JOT1D (P = 0.02) and AOT1D (P = 0.009) groups compared to their respective HC groups (n = 10). Finally, we observed no significant difference in the expression of FOXP3 and IL‐2 receptor in PI‐specific Tregs in all the groups. Conclusions Unlike polyclonal Tregs, both T1D subtypes harbor comparable frequencies of PI‐specific Tregs. Chronic antigen presentation results in a distinct memory‐like phenotype of PI‐specific Tregs in these subjects irrespective of the age of disease onset.

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“…CD8 T cells exhibit a broad range of functional and developmental states, including effector, regulatory and hypofunctional states across stages of memory differentiation. [46][47][48] Circulating islet antigen-specific CD8 T cells are well established as phenotypically heterogeneous, 11,35,37,40,[43][44][45][49][50][51][52] and encompass a spectrum of functional and developmental states. This is exemplified between two individuals with established T1D that were assayed for islet antigen-specific CD8 T cells as compared with chronic virus-specific cells (Figure 1a).…”

Section: Phenotypic and Functional Characterization Of Islet Antigen-specific Cd8 T Cells In T1dmentioning

confidence: 99%

The many faces of islet antigen‐specific CD8 T cells: clues to clinical outcome in type 1 diabetes

Wiedeman¹,

Speake²,

Long³

2021

Immunol. Cell Biol.

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Immune monitoring enables a better understanding of disease processes and response to therapy, but has been challenging in the setting of chronic autoimmunity because of unknown etiology, variable and protracted kinetics of the disease process, heterogeneity across patients and the complexity of immune interactions. To begin to parse this complexity, we focus here on type 1 diabetes (T1D) and CD8 T cells as a cell type that has features that are associated with different stages of disease, rates of progression and response to therapy. Specifically, we discuss the current understanding of the role of autoreactive CD8 T cells in disease outcome, which implicates particular CD8 functional subsets, rather than unique antigens or total number of autoreactive T cells. Next, we discuss how autoreactive CD8 T‐cell features can be reflected in measures of global CD8 T cells, and then pull these concepts together by highlighting immune therapies recently shown to modulate both CD8 T cells and disease progression. We end by discussing outstanding questions about the role of specific subsets of autoreactive CD8 T cells in disease progression and how they may be optimally modulated to treat and prevent T1D.

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Pathophysiological characteristics of preproinsulin-specific CD8+ T cells in subjects with juvenile-onset and adult-onset type 1 diabetes: A 1-year follow-up study

Cited by 7 publications

References 43 publications

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Characterization of proinsulin‐specific regulatory T cells in type 1 diabetes at different ages of onset

The many faces of islet antigen‐specific CD8 T cells: clues to clinical outcome in type 1 diabetes

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