Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice

Cebula, Anna; Kuczma, Michal; Szurek, Edyta; Pietrzak, Maciej; Savage, Natasha M.; Elhefnawy, Wessam; Rempała, Grzegorz A.; Kraj, Piotr; Ignatowicz, Leszek

doi:10.1038/s41467-019-12820-3

Cited by 24 publications

(23 citation statements)

References 50 publications

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“…The technical challenges of single-cell sequencing are nowadays being overcome by advances in single-cell, whole-transcriptome, next-generation sequencing. Such technologies have the capacity to sequence and identify the TCRs alongside the whole transcriptome and TCR–peptide–MHC dextramer binding data of tens of thousands of single cells simultaneously [ 93 , 94 ]. Numerous TCRs have been used to generate human TCR-Tregs to target various autoimmune diseases, such as T1D, MS and acquired factor VIII deficiency [ 95 , 96 , 97 ].…”

Section: Cell-based Therapiesmentioning

confidence: 99%

Treg Enhancing Therapies to Treat Autoimmune Diseases

Eggenhuizen

Ooi

2020

IJMS

137

109

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Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

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Section: Cell-based Therapiesmentioning

confidence: 99%

Treg Enhancing Therapies to Treat Autoimmune Diseases

Eggenhuizen

Ooi

2020

IJMS

137

109

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“…Thus, in the following experiments, we studied Tan cells abundance in mice that have intrinsic functional defective all Tregs or only pTregs. The TCR mini mice that lack functional Tregs due to scurfy (Sf) mutation in Foxp3 locus (SfTCR mini ) develop lethal, multiorgan systemic autoimmunity that resembles the disease in original SfC57BL6 mice with scurfy mutation 14 . Notably, in contrast to healthy B6 and TCR mini mice, the variant of these strains that harbor Sf mutation in foxp3 locus had only a few anergic CD4 + Foxp3 − CD44 + FR4 + CD73 + Tan cells in the peripheral lymphoid organs 15 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The TCR mini , A b EpTCR mini , A b 63KTCR mini strains, and mice with Foxp3 GFP reporter were described 20 . The CNS1 k/o Foxp3 GFP TCR mini , SfFoxp3 GFP (scurfy), and SfFoxp3 GFP TCR mini were communicated 14 , 41 . Cx43 k/o mice were described 24 .…”

Section: Methodsmentioning

confidence: 99%

Self and microbiota-derived epitopes induce CD4+ T cell anergy and conversion into CD4+Foxp3+ regulatory cells

et al. 2021

Self Cite

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The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4+CD44+Foxp3−CD73+FR4+ anergic (Tan) cells expands the CD4+Foxp3+ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4+CD44-Foxp3− T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.

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“…A failure of negative selection is a requirement for peripheral T cell autoreactivity in both CNS autoimmunity and other organ-specific autoimmune diseases. Even under physiological conditions, TRA presentation to thymocytes is imperfect and permits potentially autoreactive T cells to escape to the periphery [43,44]. In most circumstances, peripheral tolerance is able to compensate for incomplete thymic negative selection.…”

Section: Failure Of Negative Selectionmentioning

confidence: 99%

The contribution of thymic tolerance to central nervous system autoimmunity

Alberti

Handel

2020

Semin Immunopathol

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Autoimmune diseases of the central nervous system (CNS) are associated with high levels of morbidity and economic cost. Research efforts have previously focused on the contribution of the peripheral adaptive and innate immune systems to CNS autoimmunity. However, a failure of thymic negative selection is a necessary step in CNS-reactive T cells escaping into the periphery. Even with defective thymic or peripheral tolerance, the development of CNS inflammation is rare. The reasons underlying this are currently poorly understood. In this review, we examine evidence implicating thymic selection in the pathogenesis of CNS autoimmunity. Animal models suggest that thymic negative selection is an important factor in determining susceptibility to and severity of CNS inflammation. There are indirect clinical data that suggest thymic function is also important in human CNS autoimmune diseases. Specifically, the association between thymoma and paraneoplastic encephalitis and changes in T cell receptor excision circles in multiple sclerosis implicate thymic tolerance in these diseases. We identify potential associations between CNS autoimmunity susceptibility factors and thymic tolerance. The therapeutic manipulation of thymopoiesis has the potential to open up new treatment modalities, but a better understanding of thymic tolerance in CNS autoimmunity is required before this can be realised.

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Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice

Cited by 24 publications

References 50 publications

Treg Enhancing Therapies to Treat Autoimmune Diseases

Treg Enhancing Therapies to Treat Autoimmune Diseases

Self and microbiota-derived epitopes induce CD4+ T cell anergy and conversion into CD4+Foxp3+ regulatory cells

The contribution of thymic tolerance to central nervous system autoimmunity

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