Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens

• Published in: PLoS pathogens Vol. 17; no. 12; p. e1010085
• Main Authors: Uraki, Ryuta, Imai, Masaki, Ito, Mutsumi, Shime, Hiroaki, Odanaka, Mizuyu, Okuda, Moe, Kawaoka, Yoshihiro, Yamazaki, Sayuri
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2021; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Adaptive Immunity - immunology; Adjuvants; Animals; Antibodies; Antigen presentation; Antigen Presentation - immunology; Antigens; Antigens, Viral - immunology; Autoimmune diseases; Biology and life sciences; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell-mediated immunity; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - virology; Dendritic cells; Dendritic Cells - immunology; Depletion; Experiments; Female; Forkhead Transcription Factors - immunology; Foxp3 protein; Germinal Center - immunology; Humans; Humoral immunity; Immune Tolerance; Immunity; Immunity (cell-mediated); Immunological tolerance; Immunology; Immunoregulation; Interferon; Interleukin 2; Interleukin 2 receptors; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Maturation; Medicine and health sciences; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Proteins; Research and Analysis Methods; Rodents; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike protein; T-Lymphocytes, Regulatory - immunology; Vaccines; Vero Cells; γ-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010085

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.