Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells

Th3 CD4(+) regulatory cells were identified during the course of investigat ing mechanisms associated with oral tolerance. Different mechanisms of tole rance are induced following oral antigen administration, including active s uppression, clonal anergy and deletion. Low doses favor active suppression whereas high doses favor anergy/deletion. Th3 regulatory cells form a uniqu e T-cell subset which primarily secretes transforming growth factor (TGF)-b eta, provides help for IgA and has suppressive properties for both Th1 and Th2 cells. Th3 type cells are distinct from the Th2 cells, as CD4(+) TGF-be ta -secreting cells with suppressive properties have been generated from in terleukin (IL)-4-deficient animals. In vitro differentiation of Th3 cells f rom Th precursors from T-cell antigen receptor (TCR) transgenic mice is enh anced by culture with TGF-beta, IL-4, IL-10, and anti-IL-12. Th3 CD4(+) mye lin basic protein regulatory clones are structurally identical to Th1 encep halitogenic clones in TCR usage, NMC restriction and epitope recognition, b ut produce TGF-beta with various amounts of IL-4 and IL-10. Because Th3 reg ulatory cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. In vivo induction o f Th3 cells and low dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86 but not anti-CD80 blocks the induction of Th3 cells asso ciated with low dose oral tolerance. Th3 regulatory cells have been describ ed in other systems (e.g. recovery from experimental allergic encephalomyel itis) but may be preferentially generated following oral antigen administra tion due to the gut immunologic milieu that is rich in TGF-beta and has a u nique class of dendritic cells. CD4(+)CD25(+) regulatory T-cell function al so appears related to TGF-beta.