Ultraviolet Radiation-Induced Regulatory T Cells Not Only Inhibit the Induction but Can Suppress the Effector Phase of Contact Hypersensitivity

Abstract

Epicutaneous application of haptens to UV-exposed skin induces hapten-specific tolerance. This is mediated via regulatory T cells (Tr), as i.v. injection of T cells from UV-tolerized mice into naive animals renders the recipients unresponsive to the respective hapten. However, when UV-induced Tr are injected i.v. into sensitized mice, contact hypersensitivity (CHS) is not suppressed, suggesting that Tr inhibit the induction, but not the elicitation, of CHS and are inferior to T effector cells. As sensitization takes place in the lymph nodes, but elicitation occurs in the area of challenge, we postulated that Tr injected i.v. locate to the lymph nodes and not to the periphery and therefore only suppress the induction, not the elicitation, of CHS. Indeed, i.v. injection of Tr into sensitized mice did not inhibit CHS, although injection of Tr into the ears of sensitized mice suppressed the challenge. Inhibition was hapten specific, as injection of dinitrofluorobenzene (DNFB)-specific Tr into the ears of oxazolone (OXA)-sensitized mice did not affect challenge with OXA. However, when ears of OXA-sensitized mice were injected with DNFB-specific Tr and painted with DNFB before OXA challenge, CHS was suppressed. Inhibition correlated with the local expression of IL-10. Depletion studies and FACS analysis revealed that Tr express the lymph node-homing receptor L-selectin, but not the ligands for the skin-homing receptors E- and P-selectin, suggesting that UV-induced Tr, although able to inhibit T effector cells, do not suppress the elicitation of CHS upon i.v. injection, because they obviously do not migrate into the skin.

An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice

“…Also, UV-induced suppressor T cells have been detected in UV-treated mice, which apparently promote tumor growth by suppressing antitumor effector functions (13). Recent data suggest that UV-induced suppressor T cells belong to the CD4 ϩ CD25 ϩ regulatory T cell lineage, but little is known about the factors that regulate UV-induced suppressor T cell homeostasis or function (14). This is in contrast to the much better characterized, naturally occurring CD4 ϩ CD25 ϩ regulatory T cells.…”

“…In one investigation it was elegantly shown that NK T cells (CD3 ϩ DX5 ϩ ) from UV-irradiated donor mice can function upon transfer into naive recipients as suppressor T cells to down-regulate antitumoral immunity against injected skin tumors (50). However, recently, more evidence has been provided that CD4 ϩ CD25 ϩ T cells are able to mediate several immunoregulatory effects induced by UVR (14).…”

“…For inhibition of contact hypersensitivity responses by UV-induced suppressor T cells, IL-10 production seems to be involved (14). Recently, the tryptophan-degrading enzyme, indoleamine 2,3-dioyxgenase (IDO), has been identified to play a role in the regulation of T cell function (51).…”

“…There is currently increasing evidence that UV-induced suppressor T cells belong to the CD4 ϩ CD25 ϩ regulatory T cell lineage (14). Additionally, it was shown that the peripheral homeostasis of naturally occurring CD4 ϩ CD25 ϩ regulatory T cells is modulated by molecules of the B7 family (17,38).…”

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

“…4 Although some UVB regimens can activate natural regulatory T cells or induce Ag-specific regulatory CD4 ϩ CD25 ϩ T cells to suppress CD8 T-cell immunity, 5,24 we found that suberythemal doses of UVB, delivered at a systemic site from Ag, do not induce functional CD4 ϩ CD25 ϩ regulatory T cells that inhibit subsequent Ag-specific CD8 T-cell responses and DTH reactions. These experiments cannot exclude the ac- The percentage-specific lysis from an in vivo cytotoxicity assay was determined 7 days after immunization in mice given empty (E) or T4N5 (T) Lipo.…”