Transient Treg-cell depletion in adult mice results in persistent self-reactive CD4(+) T-cell responses

Eur J Immunol. 2014 Dec;44(12):3621-31. doi: 10.1002/eji.201344432. Epub 2014 Nov 2.

Abstract

Depletion of Foxp3(+) CD4(+) regulatory T cells (Treg) in adults results in chronic inflammation and autoimmune disease. However, the impact of transient Treg-cell depletion on self-reactive responses is poorly defined. Here, we studied the effect of transient depletion of Treg cells on CD4(+) T-cell responses to endogenous self-antigens. Short-term ablation of Treg cells in mice resulted in rapid activation of CD4(+) T cells, increased percentage of IFN-γ(+) and Th17 cells in lymphoid organs, and development of autoimmune gastritis. To track self-reactive responses, we analyzed the activation of naïve gastric-specific CD4(+) T cells. There was a dramatic increase in proliferation and acquisition of effector function of gastric-specific T cells in the stomach draining LNs of Treg-cell-depleted mice, compared with untreated mice, either during Treg-cell depletion or after Treg-cell reconstitution. Moreover, the hyperproliferation of gastric-specific T cells in the Treg-cell-ablated mice was predominantly antigen-dependent. Transient depletion of Treg cells resulted in a shift in the ratio of peripheral:thymic Treg cells in the reemerged Treg-cell population, indicating an altered composition of Treg cells. These findings indicate that transient Treg-cell depletion results in ongoing antigen-driven self-reactive T-cell responses and emphasize the continual requirement for an intact Treg-cell population.

Keywords: Autoimmune gastritis; Foxp3; Gastric H/K ATPase; Immune homeostasis; Regulatory T (Treg) cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / genetics
  • Autoantigens / immunology
  • Autoimmunity*
  • Cell Proliferation*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Depletion*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Stomach / immunology
  • Stomach / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Autoantigens
  • Interferon-gamma