Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator

doi:10.1073/pnas.1533207100

Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator

^*Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA 30322; ^†DiBiT, San Raffaele Scientific Institute, Milan 20132, Italy; and ^‡Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110

Communicated by David M. Kipnis, Washington University School of Medicine, St. Louis, MO, May 27, 2003 (received for review March 13, 2003)

Abstract

Expansion of the pool of tumor necrosis factor (TNF)-α-producing T cells is instrumental for the bone loss induced by estrogen deficiency, but the responsible mechanism is unknown. Here we show that ovariectomy up-regulates IFN-γ-induced class II transactivator, a multitarget immune modulator, resulting in increased antigen presentation by macrophages, enhanced T cell activation, and prolonged lifespan of active T cells. Up-regulation of class II transactivator derives from increased production of IFN-γ by T helper 1 cells, resulting from enhanced secretion of IL-12 and IL-18 by macrophages. The resulting T cell expansion and bone loss are prevented in vivo by both blockade of antigen presenting cell-induced T cell activation, and silencing of IFN-γ receptor signaling. Thus, increased IFN-γ-induced class II transactivator expression and the resulting enhanced T cell proliferation and lifespan are critical to the bone wasting effect of estrogen deficiency.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: rpacifi{at}emory.edu.
Abbreviations: TNF, tumor necrosis factor α; MHCII, MHC class II; ovx, ovariectomy, ovariectomized; BM, bone marrow; CIITA, class II transactivator; Ag, antigen; APC, Ag-presenting cell; Mϕ, macrophage; DC, dendritic cell; AICD, activation-induced cell death; TCR, T cell receptor; BMD, bone mineral density; T_H, T helper; IFN-γR, IFN-γ receptor; PE, phycoerythrin; FACS, fluorescence-activated cell sorting.