Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity

Sprouse, Maran L.; Shevchenko, Ivan; Scavuzzo, Marissa A.; Joseph, Faith M.; Lee, Thomas; Blum, Samuel I.; Borowiak, Malgorzata; Bettini, Matthew L.

doi:10.4049/jimmunol.1700156

Cited by 35 publications

(32 citation statements)

References 39 publications

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“…Apparently Tregs with low-affinity TCR are more likely to use non-TCR-dependent suppressive mechanisms in the absence of strong TCR signaling in response to humoral inflammatory factors, while high-affinity Tregs preferentially upregulate TCR-dependent regulatory molecules, such as CTLA-4, TIGIT, and IL-10. Nevertheless, both types of cells have suppressive potential and support autotolerance and immune equilibrium (31,57,58).…”

Section: Treg Heterogeneitymentioning

confidence: 99%

Treg Heterogeneity, Function, and Homeostasis

2020

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Section: Treg Heterogeneitymentioning

confidence: 99%

Treg Heterogeneity, Function, and Homeostasis

2020

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“…Such an assumption is further supported by a study using a NOD‐based model of autoimmune diabetes. This study demonstrated that T reg populations with a low‐affinity TCR for their cognate antigen preferentially expressed Amphiregulin, preferentially localized to the site of inflammation and functioned there in an antigen‐independent way . Thus, taken together, the combined expression of T1/ST2 and EGFR may enable tissue‐resident T reg populations to function in a MHC‐II‐independent way.…”

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinmentioning

confidence: 82%

“…This study demonstrated that T reg populations with a low-affinity TCR for their cognate antigen preferentially expressed Amphiregulin, preferentially localized to the site of inflammation and functioned there in an antigen-independent way. 57 Thus, taken together, the combined expression of T1/ST2 and EGFR may enable tissue-resident T reg populations to function in a MHC-II-independent way. In Th2 cells, the induced expression of Amphiregulin, in an autocrine way, enabled the formation of such hetero-complexes between EGFR and T1/ST2, and only upon expression of Amphiregulin could activated Th2 cells function in a MHC-II-independent way.…”

Section: The Function Of Regulatory T-cell-derived Amphiregulinmentioning

confidence: 99%

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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“…A further layer of variables, not addressed in this analysis, lies in the fact that multiple different clones of T cells may have TCR that bind the same TCEM peptide motif but with different affinities, and hence different dwell times, and that may trigger different cytokine outcomes ( 106 ). Higher binding affinity, consistent with higher suppressive indices, is reportedly more prone to generate IL-10 upregulation ( 106 , 107 ). Binding based on less than five amino acid residues, or so-called “near neighbor” binding, further expands the possibilities for lesser binding affinities ( 108 ).…”

Section: Discussionmentioning

confidence: 99%

A Role for Epitope Networking in Immunomodulation by Helminths

Homan¹,

Bremel²

2018

Front. Immunol.

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Helminth infections, by nematodes, trematodes, or cestodes, can lead to the modulation of host immune responses. This allows long-duration parasite infections and also impacts responses to co-infections. Surface, secreted, excreted, and shed proteins are thought to play a major role in modulation. A commonly reported feature of such immune modulation is the role of T regulatory (Treg) cells and IL-10. Efforts to identify helminth proteins, which cause immunomodulation, have identified candidates but not provided clarity as to a uniform mechanism driving modulation. In this study, we applied a bioinformatics systems approach, allowing us to analyze predicted T-cell epitopes of 17 helminth species and the responses to their surface proteins. In addition to major histocompatibility complex (MHC) binding, we analyzed amino acid motifs that would be recognized by T-cell receptors [T-cell-exposed motifs (TCEMs)]. All the helminth species examined have, within their surface proteins, peptides, which combine very common TCEMs with predicted high affinity binding to many human MHC alleles. This combination of features would result in large cognate T cell and a high probability of eliciting Treg responses. The TCEMs, which determine recognition by responding T-cell clones, are shared to a high degree between helminth species and with Plasmodium falciparum and Mycobacterium tuberculosis, both common co-infecting organisms. The implication of our observations is not only that Treg cells play a significant role in helminth-induced immune modulation but also that the epitope specificities of Treg responses are shared across species and genera of helminth. Hence, the immune response to a given helminth cannot be considered in isolation but rather forms part of an epitope ecosystem, or microenvironment, in which potentially immunosuppressive peptides in the helminth network via their common T-cell receptor recognition signals with T-cell epitopes in self proteins, microbiome, other helminths, and taxonomically unrelated pathogens. Such a systems approach provides a high-level view of the antigen-immune system signaling dynamics that may bias a host’s immune response to helminth infections toward immune modulation. It may indicate how helminths have evolved to select for peptides that favor long-term parasite host coexistence.

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Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity

Cited by 35 publications

References 39 publications

Treg Heterogeneity, Function, and Homeostasis

Treg Heterogeneity, Function, and Homeostasis

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

A Role for Epitope Networking in Immunomodulation by Helminths

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