Tolerogenic APC generate CD8+ T regulatory cells that modulate pulmonary interstitial fibrosis.
Transforming growth factor-beta2-treated Ag-pulsed APC mimic APC from the immune privileged eye, and provide signals that generate regulatory T (Tr) cells and mediate peripheral tolerance. We postulated that TGF-beta2-treated Ag-pulsed APC (tolerogenic APC (tol-APC)) might also orchestrate regulation of immune mediated pathogenesis in nonimmune privileged tissues such as the lung. We used an adoptive transfer model of autoimmune pulmonary interstitial fibrosis called hapten immune pulmonary interstitial fibrosis (ADT-HIPIF) in this study. Mice that received 2,4,6-trinitrobenzene sulfonic acid-sensitized cells and challenged (intratracheally) with the hapten developed pulmonary interstitial fibrosis. However, transfer (i.v.) of TGF-beta2-treated 2,4,6-trinitrobenzene sulfonic acid-pulsed bone marrow-derived APC (tol-APC) to experimental mice 1 day after intratracheal challenge reduced the collagen deposition in the interstitium of the lung that usually follows challenge. Furthermore, ADT-HIPIF mice that received tol-APC developed Ag-specific efferent CD8+ Tr cells. Adoptive transfer of the Tr cells to another set of presensitized mice mediated suppression of the efferent phase of Th1 immune response and the subsequent immune dependent pulmonary interstitial fibrosis. Thus, tol-APC induced efferent CD8+ Tr cells in immune mice, and the regulation of the immune response limited the development of autoimmune pulmonary fibrosis in sensitized and pulmonary-challenged mice. Because ADT-HIPIF shares etiological and pathological characteristics with a variety of human immune inflammatory conditions in the lung that eventuate into interstitial fibrosis, these studies provide insight into potential therapy to alter the course of pulmonary fibrosis in humans.
Zhang-Hoover
Jie
J
Schepens Eye Research Institute and Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
Stein-Streilein
Joan
J
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D006241:Haptens / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053781:Transforming Growth Factor beta2; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
D006241:Haptens; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D014302:Trinitrobenzenesulfonic Acid