PLZF(+) Innate T Cells Support the TGF-β-Dependent Generation of Activated/Memory-Like Regulatory T Cells.
PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether PLZF(+) innate T cells also affect the development and function of Foxp3(+) regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant PLZF(+) CD4 T cells and invariant natural killer T cells, respectively, revealed that Foxp3(+) T cells in these mice exhibited a CD103(+) activated/memory-like phenotype. The frequency of CD103(+) regulatory T cells was considerably decreased in PLZF(+) cell-deficient CIITA(Tg)Plzf(lu/lu) and BALB/c.CD1d(-/-) mice as well as in an IL-4-deficient background, such as in CIITA(Tg)IL-4(-/-) and BALB/c.lL-4(-/-) mice, indicating that the acquisition of an activated/memory-like phenotype was dependent on PLZF(+) innate T cells and IL-4. Using fetal thymic organ culture, we further demonstrated that IL-4 in concert with TGF-β enhanced the acquisition of the activated/memory-like phenotype of regulatory T cells. In functional aspects, the activated/memory-like phenotype of Treg cells was directly related to their suppressive function; regulatory T cells of CIITA(Tg)PIV(-/-) mice more efficiently suppressed ovalbumin-induced allergic airway inflammation compared with their counterparts from wild-type mice. All of these findings suggest that PLZF(+) innate T cells also augmented the generation of activated/memory-like regulation via IL-4 production.
Postgraduate Course of Translational Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.
Byung Hyun
BH
Kang
Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Department of Pathology, Seoul National University Bundang Hospital, Sungnam 13620, Korea.
Hyo Jin
HJ
Park
Postgraduate Course of Translational Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.
Hi Jung
HJ
Park
Postgraduate Course of Translational Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.
Jae-Ii
JI
Lee
Postgraduate Course of Translational Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.
Seong Hoe
SH
Park
Postgraduate Course of Translational Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.|Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea.
Kyeong Cheon
KC
Jung
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology; D009924:Organ Culture Techniques; D010641:Phenotype; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D013154:Spleen / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016212:Transforming Growth Factor beta; C513267:Zbtb16 protein, mouse; D015847:Interleukin-4
IL-4; PLZF; regulatory T lymphocyte