Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices

Daley, Stephen R.; Koay, Hui-Fern; Dobbs, Kerry; Bosticardo, Marita; Wirasinha, Rushika C.; Pala, Francesca; Castagnoli, Riccardo; Rowe, Jared H.; Bruin, L. M. Ott de; Keleş, Sevgi; Lee, Yu Nee; Somech, Raz; Holland, Steven M.; Delmonte, Ottavia M.; Draper, Debbie; Maxwell, Sandra; Niemela, Julie E.; Stoddard, Jennifer; Rosenzweig, Sergio D.; Poliani, Pietro Luigi; Capo, Valentina; Villa, Anna; Godfrey, Dale I.; Notarangelo, Luigi D.

doi:10.1016/j.jaci.2019.03.022

Cited by 32 publications

(48 citation statements)

References 9 publications

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“…The pre-symptomatic identification of infants with SCID through newborn screening has significantly improved the clinical management of these conditions [ 84 ]. CID is also characterized by increased susceptibility to recurrent and life-threatening infections; however, because of residual T cell function, clinical onset is often delayed (>1 year of age) as compared to SCID, and disease severity may also be decreased [ 85 , 86 , 87 ]. Furthermore, at variance with SCID, CID is also characterized by an increased risk of immune dysregulation and malignancy.…”

Section: Gut Microbiota–host Interactions In Human Inborn Errors Omentioning

confidence: 99%

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Castagnoli

Pala

Bosticardo

et al. 2021

IJMS

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Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host’s innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.

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Section: Gut Microbiota–host Interactions In Human Inborn Errors Omentioning

confidence: 99%

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Castagnoli

Pala

Bosticardo

et al. 2021

IJMS

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“…This characteristic repertoire was recently also reported for type A IELps in mice. Furthermore, a high percentage of TCRs with a high hydrophobic index and cysteine index were observed in the human and murine IELps, in line with the self-reactivity observed in the IELp population [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 71%

Human Thymic CD10+ PD-1+ Intraepithelial Lymphocyte Precursors Acquire Interleukin-15 Responsiveness at the CD1a– CD95+ CD28– CCR7– Developmental Stage

Billiet

Goetgeluk

Bonte

et al. 2020

IJMS

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Human thymic CD8αα+ CD10+ PD-1+ αβ T cells selected through early agonist selection have been proposed as the putative thymic precursors of the human CD8αα+ intestinal intraepithelial lymphocytes (IELs). However, the progeny of these thymic precursor cells in human blood or tissues has not yet been characterized. Here, we studied the phenotypical and transcriptional differentiation of the thymic IEL precursor (IELp) lineage upon in vitro exposure to cytokines prominent in the peripheral tissues such as interleukin-15 (IL-15) and the inflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). We showed that only the CD1a− fraction of the CD10+ PD-1+ IELp population was able to proliferate with IL-15, suggesting that this subset had acquired functionality. These cells downregulated PD-1 expression and completely lost CD10 expression, whereas other surface markers such as CD95 and CXCR3 remained highly expressed. RNA-seq analysis of the IL-15-cultured cells clearly showed induction of innate-like and effector genes. Induction of the cytotoxic machinery by the CD10+ PD-1+ population was acquired in the presence of IL-15 and was further augmented by inflammatory cytokines. Our data suggest that only the CD1a− CD10+ PD-1+ population exits the thymus and survives in the periphery. Furthermore, PD-1 and CD10 expression is not an intrinsic property of this lineage, but rather characterizes a transient stage in differentiation. CD95 and CXCR3 expression combined with the absence of CD28, CCR7, and CD6 expression might be more powerful markers to define this lineage in the periphery.

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“…30 We had previously shown that abnormalities of thymic architecture and TEC composition in humans and mice with RAG defects 24,[31][32][33] are associated with molecular signatures of self-reactivity in the peripheral T-cell repertoire. 34,35 Restoration of TEC maturation may therefore also have important implications for correction of the immune dysregulation that is often associated with RAG deficiency. Finally, conditioning of Rag1-F971L mice with CD45-SAP led to marked improvement of the autoantibody profile, especially when combined with low-dose TBI, indicating that this approach allows high levels of multilineage chimerism and corrects breakdown of immune tolerance.…”

Section: Discussionmentioning

confidence: 99%