TGF-β-Producing CD4+ Mediastinal Lymph Node Cells Obtained from Mice Tracheally Tolerized to Ovalbumin (OVA) Suppress Both Th1- and Th2-Induced Cutaneous Inflammatory Responses to OVA by Different Mechanisms

Abstract

Advances in the treatment of allergic disorders require elucidation of the autoregulatory immune systems induced in averting detrimental inflammatory responses against invading foreign Ags. We previously reported that excessive Ags intruding through the airway mucosa induce a subset of regulatory CD4+ T cells secreting TGF-β in the regional mediastinal lymph nodes (MLNs), which inhibits Th2 cells and subsequent eosinophilic inflammation in the trachea. In the present experiments we examined whether and in what mechanisms TGF-β-secreting CD4+ T cells in the MLNs regulate Th cell-mediated skin inflammation using a previously established murine model. Th1 or Th2 cells injected s.c. into ear lobes of naive mice induced swelling, whereas the concomitant local injection of MLN cells suppressed the inflammation. The suppressor activities of MLN cells were markedly neutralized by anti-TGF-β mAb and were mimicked by rTGF-β. The MLN cell- and rTGF-β-induced inhibition was reversed by anti-IL-10 mAb significantly in Th1-induced inflammation and only partially in Th2-induced inflammation. rIL-10 reduced Th-induced ear swelling, although higher doses of rIL-10 were required in Th2-induced one. Thus, allergen-specific TGF-β-producing CD4+ T cells induced in the respiratory tract controlled cutaneous inflammatory responses by Th1 or Th2 cells either directly by TGF-β or indirectly through IL-10 induction. From a clinical standpoint, these observations might explain the mechanism of spontaneous regression in some patients with atopic dermatitis, which exhibits both Th1- and Th2-mediated skin inflammation in response to airborne protein Ags.

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

“…However, whether oral tolerance also inhibited Th2 differentiation in LNs draining the site of epicutaneous sensitization was not examined (72). Moreover, studies examining the effect of airway tolerance on inflammatory responses in the skin have done so by transferring tolerizing LN cells mixed with Th1 or Th2 effector cells directly into the site of Ag injection (15) and, thus, do not adequately address the issues explored in this manuscript, namely the compartmentalization of immune tolerance. In this study, we examined the impact of respiratory mucosal tolerance on cutaneous as well as GI mucosal responses, in an experimental system in which de novo sensitization specifically occurred in LNs distant to the site of tolerance induction, and in the same animal.…”

“…Previous studies have reported a vital role for CD4 ϩ T cells in the induction of immune tolerance following intratracheal (15,16), i.n. (48 -52), aerosolized (18,37,53), oral (54,55), or i.v.…”

“…Of note, there are studies that have shown tolerance to operate without suppressing proliferation (78); thus, it may be possible that the thoracic LNs do in fact harbor tolerogenic activity, but by a mechanism other than suppression. In support of this, LN-derived populations have been used to transfer tolerance to naive recipients, but either required substantially higher cell numbers or used activated/proliferating CD4 ϩ T cells harvested from LNs actively undergoing tolerance induction and, importantly, not LNs that once harbored tolerance induction (15,49). It may be possible that tolerized T cells are not imprinted with a tissue-selective tropism, but rather are capable of recirculating between mucosal and nonmucosal LNs/tissues.…”

“…Immune tolerance has been shown to arise via several mechanisms, including the induction of anergy (9 -11), clonal deletion of Ag-specific lymphocytes (12), or active immune regulation mediated by regulatory cells secreting TGF-␤ (13)(14)(15)(16)(17), , or IL-10 (21,22). The dysregulation of these tolerogenic processes plays an important role in the emergence of aberrant immune responses to harmless environmental or self Ags (23,24).…”

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model

“…To clarify the relationship between LPR and eosinophils, we previously succeeded in developing an animal skin inflammation model. With this model, we could evaluate the contribution of protein Ag-specific Th1 or Th2 cells and found that eosinophils and neutrophils play critical roles in producing ear swelling induced by the Th2 and Th1 cells, respectively [5,6]. To investigate the pathomechanisms of AD, other laboratories have employed murine models of AD [7,8].…”