Alveolar type II epithelial cells present antigen to CD4(+) T cells and induce Foxp3(+) regulatory T cells

Am J Respir Crit Care Med. 2009 Mar 1;179(5):344-55. doi: 10.1164/rccm.200804-592OC. Epub 2008 Dec 18.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology*
  • Autoantigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / immunology*
  • Hemagglutinins / immunology
  • Histocompatibility Antigens Class II / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Pneumonia / immunology*
  • Pneumonia / pathology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / immunology


  • Autoantigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hemagglutinins
  • Histocompatibility Antigens Class II
  • Transforming Growth Factor beta