Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Choi, John Y.; Eskandari, Siawosh K.; Cai, Shanshan; Sulkaj, Ina; Assaker, Jean Pierre; Allos, Hazim; Alhaddad, Juliano B.; Muhsin, Saif A.; Alhussain, Eman; Mansouri, Amr; Yeung, Melissa Y.; Seelen, Marc A.; Kim, Hye-Jung; Cantor, Harvey; Azzi, Jamil

doi:10.1073/pnas.1918950117

Cited by 23 publications

(17 citation statements)

References 22 publications

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“…A subset of CD8+ Treg cells recognizes Qa-1, which is essential for the maintenance of self-tolerance (Choi et al, 2020). Qa-1 inhibits NK cells-mediated T-cell killing via suppressing CD8+CD103+ Treg-cells.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

Huang

Yang

Tolstikov³

et al. 2020

Preprint

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29Objective: Celiac disease (CD) is an immune-mediated disease characterized by small intestinal 30 inflammation. CD is associated with HLA-DQ2 and HLA-DQ8 haplotypes, however, genetics 31 alone cannot explain the increasing incidence rates. The main goal of this study was to determine 32 the role of the gut microbiota in CD pathogenesis in the first five years of life. 33Design: We conducted a longitudinal study focusing on three developmental phases of the gut 34 microbiota (ages 1, 2.5 and 5 years). The fecal samples were obtained from 16 children who 35 developed CD and 16 matched controls. We used 16S sequencing combined with functional 36 analysis, flow cytometry, immunoglobulin A (IgA) sequencing (IgA-seq), and plasma 37 metabolomics to determine a microbial link to CD pathogenesis. 38 Results:We identified a distinct gut microbiota composition in CD progressors (CDP, children 39 who developed CD during or after their gut microbiota were sampled) in each developmental 40 phase. Pathogenesis and inflammation-related microbial pathways were enriched in CDP. 41 Moreover, they had significantly more IgA coated bacteria and the IgA targets were significantly 42 different compared to controls. Proinflammatory and pathogenesis-related metabolic pathways 43 were enriched in CDP. Further, we identified inflammatory metabolites, particularly microbiota-44 derived taurodeoxycholic acid (TDCA) as increased in CDP. 45 Conclusion:Our study defines an inflammatory gut microbiota for the CDP including its 46 composition, function, IgA response and related plasma metabolites. The inflammatory nature of 47 CD gut microbiota during development is potentially related to the onset of the disease. 48Targeting inflammatory bacteria in this critical window could affect the pathogenesis and 49 prognosis of CD. 50 51 Significance of this study 52What is already known on this subject? 53• Celiac Disease (CD) is a gluten induced immune-mediated disease in genetically 54 predisposed individuals. 55• CD incidence is increasing worldwide which genetics alone cannot explain. Previous 56 studies have shown that the gut microbiota of CD patients differ from that of healthy 57 populations. However, the role of the microbiome in CD pathogenesis and its role in 58 chronic inflammation is yet be established. 59What are the new findings? 60• In a prospective longitudinal study in children using samples representing all three phases 61 of gut microbiota development (ages 1, 2.5 and 5), we identified significant differences in 62 the composition and function of gut microbiota at each phase. Pathogenesis and 63 inflammation-related functions are enriched in the gut microbiome of CD progressors. 64• We applied IgA-sequencing to identify inflammatory bacteria in both healthy subjects 65 and CD progressors. Flow Cytometry analysis identified more IgA coated bacteria at ages 66 1 and 5 in CD progressors, indicating an early inflammatory response. CD bacterial IgA 67 targets also differed significantly from healthy controls. 68• We analyzed plasma meta...

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Section: Discussionmentioning

confidence: 99%

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

Huang

Yang

Tolstikov³

et al. 2020

Preprint

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“…In addition to abovementioned EAE model (19,36,37), CD8 + CD122 hi Ly49 + Tregs have documented functions in various settings, including colitis (38,39), hepatitis (40), arthritis (41), diabetes (42,43), viral infection (44), tumor immunity (45), atherogenesis (46) and organ transplantation (47). The best demonstrated role of CD8 + Tregs is to suppress GC reaction.…”

Section: Cd122 Hi Ly49 + Cd8 + Treg -Discovery and Functionmentioning

confidence: 99%

CD8+ Regulatory T Cell – A Mystery to Be Revealed

Mishra

Srinivasan

et al. 2021

Front. Immunol.

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Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3+CD4+ Tregs are well established, much of CD8+ Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8+ T cells have been named “CD8+ Treg” and mainly focus on CD122hiLy49+CD8+ Tregs present in naïve mice. CD122hiLy49+CD8+ Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-β (Transforming growth factor-β) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8+ Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8+ Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4+ TFR (follicular regulatory T cells) and CD8+ Tregs.

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“…Similarly to Qa‐1 −/− mice, Qa‐1 D277K mice develop lupus‐like autoimmune phenotype with tissue‐specific autoantibodies and lymphoid infiltration of peripheral organs [135, 141]. They also show enhanced susceptibility to EAE [141] and faster rejection of allograft associated with an increased production of antibodies specific for the donor organ compared to WT recipients [142]. It has been shown that these effects are dependent on IFN‐γ, perforin, and IL‐15, but not on FasL [135, 141].…”

Section: Qa‐1‐restricted T Cellsmentioning

confidence: 99%

“…Another obstacle is that there is no consensus about how this population can be phenotypically distinguished from other CD8 + T cells. Whereas one study described Qa‐1‐restricted CD8 + T cells as CD44 + CXCR5 + [142], another study characterized Qa‐1‐restricted T cells as CD8 + CD122 + CD44 + Ly49 + , which connects them to the previously described CD8 + CD122 + cells [47]. Importantly, Qa‐1‐restricted CD8 + CD44 + CD122 + Ly49 + Tregs express Helios, a transcription factor essential for the maintenance of their suppressive function [134].…”

Section: Qa‐1‐restricted T Cellsmentioning

confidence: 99%

CD8⁺ Tregs revisited: A heterogeneous population with different phenotypes and properties

et al. 2021

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Regulatory T cells (Tregs) play a key role in the peripheral self‐tolerance and preventing autoimmunity. While classical CD4+ Foxp3+ Tregs are well established, their CD8+ counterparts are still controversial in many aspects including their phenotypic identity and their mechanisms of suppression. Because of these controversies and because of only a limited number of studies documenting the immunoregulatory function of CD8+ Tregs in vivo, the concept of CD8+ Tregs is still not unanimously accepted. We propose that any T‐cell subset considered as true regulatory must be distinguishable from other cell types and must suppress in vivo immune responses via a known mechanism. In this article, we revisit the concept of CD8+ Tregs by focusing on the characterization of individual CD8+ T‐cell subsets with proposed regulatory capacity separately. Therefore, we review the phenotype and function of CD8+ FOXP3+ T cells, CD8+ CD122+ T cells, CD8+ CD28low/− T cells, CD8+ CD45RClow T cells, T cells expressing CD8αα homodimer and Qa‐1‐restricted CD8+ T cells to show whether there is sufficient evidence to establish these subsets as bona fide Tregs. Based on the intrinsic ability of CD8+ Treg subsets to promote immune tolerance in animal models, we elaborate on their potential use in clinics.

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Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Cited by 23 publications

References 22 publications

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

CD8+ Regulatory T Cell – A Mystery to Be Revealed

CD8⁺ Tregs revisited: A heterogeneous population with different phenotypes and properties

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Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Cited by 23 publications

References 22 publications

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

CD8+ Regulatory T Cell – A Mystery to Be Revealed

CD8+ Tregs revisited: A heterogeneous population with different phenotypes and properties

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Product

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CD8⁺ Tregs revisited: A heterogeneous population with different phenotypes and properties