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Local "on-demand" generation and function of antigen-specific Foxp3+ regulatory T cells.

ABSTRACT: Extrathymically derived regulatory T cells (iTregs) protect against autoimmunity to tissue-specific Ags. However, whether Ag-specific iTreg generation and function is limited to secondary lymphoid tissue or whether it can occur within the tissue-specific local environment of the cognate Ag remains unresolved. Mice expressing ?-galactosidase (?gal) on a retina-specific promoter (?gal mice) in conjunction with mice expressing GFP and diphtheria toxin (DTx) receptor (DTR) under control of the Foxp3 promoter, and ?gal-specific TCR transgenic (BG2) mice were used to examine this question. Local depletion (ocular DTx), but not systemic depletion (i.p. DTx), of ?gal-specific iTregs enhanced experimental autoimmune uveoretinitis induced by activated ?gal-specific effector T cells. Injections of small amounts of ?gal into the anterior chamber of the eye produced similar numbers of ?gal-specific iTregs in the retina whether the mouse was depleted of pre-existing, circulating Tregs. Taken together, these results suggest that protection from tissue-specific autoimmunity depends on the function of local Ag-specific iTregs and that the retina is capable of local, "on-demand" iTreg generation that is independent of circulating Tregs.

SUBMITTER: McPherson SW

PROVIDER: S-EPMC3646944 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Local "on-demand" generation and function of antigen-specific Foxp3+ regulatory T cells.

McPherson Scott W SW Heuss Neal D ND Gregerson Dale S DS

Journal of immunology (Baltimore, Md. : 1950) 20130412 10

Extrathymically derived regulatory T cells (iTregs) protect against autoimmunity to tissue-specific Ags. However, whether Ag-specific iTreg generation and function is limited to secondary lymphoid tissue or whether it can occur within the tissue-specific local environment of the cognate Ag remains unresolved. Mice expressing β-galactosidase (βgal) on a retina-specific promoter (βgal mice) in conjunction with mice expressing GFP and diphtheria toxin (DTx) receptor (DTR) under control of the Foxp3 ...[more]

PMID: 23585681

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Project description:Regulatory T (Treg) cells, which constitute about 5-10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.

Dataset Information

Local "on-demand" generation and function of antigen-specific Foxp3+ regulatory T cells.

Publications

Local "on-demand" generation and function of antigen-specific Foxp3+ regulatory T cells.

Similar Datasets

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