IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin.
Regulatory T cells (Tregs) are crucial for the induction and maintenance of self-tolerance and are present in peripheral tissues such as skin and gut under normal, noninflamed conditions. We report isolation and expansion of the Treg population resident in normal human skin. Cutaneous Tregs expressed high levels of CD25, L-selectin, GITR, FOXP3, and intracellular CTLA-4, low levels of CD69, and high levels of the skin-homing addressins CLA, CCR4, and CCR6. Skin Tregs suppressed the proliferation of CD25(lo) T cells from the same skin sample in response to CD3 and CD28 antibodies. Suppression was dependent on cell contact and not affected by neutralizing antibodies to interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Surprisingly, cutaneous Tregs proliferated in an antigen-independent manner when cultured in contact with dermal fibroblasts and IL-15, conditions similar to those found in chronically inflamed skin. We hypothesize that local proliferation of Tregs may occur within inflamed skin and could serve as a brake for cutaneous inflammation as well as a mechanism for the homeostatic proliferation of natural Tregs that has been observed within intact organisms.
Clark
Rachael A
RA
Department of Dermatology, Brigham and Women's Hospital and the Harvard Skin Disease Research Center, Boston, MA 02115, USA. rclark1@partners.org
Kupper
Thomas S
TS
D000243:Adenosine Deaminase / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers; D001769:Blood / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002450:Cell Communication; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D003872:Dermatitis / Q000276:immunology / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology; D005347:Fibroblasts / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006023:Glycoproteins / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology; D019409:Interleukin-15 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D018448:Models, Immunological; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D000099192:CD69 Antigens
D000243:Adenosine Deaminase; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D015415:Biomarkers; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D018819:Dipeptidyl Peptidase 4; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006023:Glycoproteins; D016753:Interleukin-10; D019409:Interleukin-15; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D000099192:CD69 Antigens; C515354:CCR4 protein, human; C106311:CCR6 protein, human; C063419:CTAGE1 protein, human; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; C491405:TNFRSF18 protein, human; C042807:DPP4 protein, human