BACKGROUND: Type 3 innate lymphoid cells (ILC3s) are involved in maintenance of mucosal
homeostasis; however, their role in immunoregulation has been unknown. Immature transitional
regulatory B (itBreg) cells are innate-like B cells with immunosuppressive properties,
and the in vivo mechanisms by which they are induced have not been fully clarified.
OBJECTIVE: We aimed to investigate the ILC3-B-cell interaction that probably takes
place in human tonsils. METHODS: ILC3s were isolated from peripheral blood and palatine
tonsils, expanded, and cocultured with naive B cells. Tonsillar ILC3s and regulatory
B cells were visualized with immunofluorescence histology. ILC3 frequencies were measured
in tonsil tissue of allergic and nonallergic patients and in peripheral blood of allergic
asthmatic patients and healthy control subjects. RESULTS: A mutually beneficial relationship
was revealed between ILC3s and B cells: ILC3s induced IL-15 production in B cells
through B cell-activating factor receptor, whereas IL-15, a potent growth factor for
ILC3s, induced CD40 ligand (CD40L) expression on circulating and tonsillar ILC3s.
IL-15-activated CD40L(+) ILC3s helped B-cell survival, proliferation, and differentiation
of IL-10-secreting, PD-L1-expressing functional itBreg cells in a CD40L- and B cell-activating
factor receptor-dependent manner. ILC3s and regulatory B cells were in close connection
with each other in palatine tonsils. ILC3 frequency was reduced in tonsil tissue of
allergic patients and in peripheral blood of allergic asthmatic patients. CONCLUSION:
Human CD40L(+) ILC3s provide innate B-cell help and are involved in an innate immunoregulatory
mechanism through induction of itBreg cell differentiation, which takes place in palatine
tonsils in vivo. This mechanism, which can contribute to maintenance of immune tolerance,
becomes insufficient in allergic diseases.