Alveolar type II epithelial cells present antigen to CD4(+) T cells and induce Foxp3(+) regulatory T cells.
BACKGROUND
Although the contribution of alveolar type II epithelial cells (AECIIs) in respiratory immunity has become increasingly appreciated, their precise function in the induction and regulation of T-cell reactivity to self-antigen remains poorly understood.


OBJECTIVE
To investigate the role of AECII in the initiation of T-cell reactivity to alveolar self-antigen, and to clarify their function in the peripheral induction of Foxp3(+) regulatory CD4(+) T cells.


METHODS
To dissect the complex cellular and molecular functions of AECIIs in lung inflammation and immune regulation, we use a transgenic mouse model for CD4(+) T-cell-mediated pulmonary inflammation.


RESULTS
Here we report that AECIIs present endogenously expressed antigen on major histocompatibility complex class II molecules to CD4(+) T cells. Epithelial antigen display was sufficient to induce primary T-cell activation and pulmonary inflammation. Upon inflammation, AECIIs induce the differentiation of Foxp3(+) regulatory T cells by a mechanism involving antiproliferative soluble factors, including transforming growth factor (TGF)-beta. Whereas, in acute inflammation, TGF-beta appears to be the dominant factor to induce regulatory T cells, other AECII-derived factors can substitute for and/or synergize with TGF-beta in chronic pulmonary inflammations.


CONCLUSIONS
AECIIs are capable of priming naive CD4(+) T cells, demonstrating an active participation of these cells in respiratory immunity. Moreover, AECIIs display as yet unrecognized functions in balancing inflammatory and regulatory T-cell responses in the lung by connecting innate and adaptive immune mechanisms to establish peripheral T-cell tolerance to respiratory self-antigen.
Gereke
Marcus
M
Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Jung
Steffen
S
Buer
Jan
J
Bruder
Dunja
D
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology*; D006388:Hemagglutinins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology
D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006388:Hemagglutinins; D000949:Histocompatibility Antigens Class II; D016212:Transforming Growth Factor beta