T-bet-dependent expression of osteopontin contributes to T cell polarization

Abstract

The osteopontin (Opn) glycoprotein has been implicated in diverse physiological processes, including vascularization, bone formation, and inflammatory responses. Studies of its role in immune responses has suggested that Opn can set the early stage of type-1 immune (cell-mediated) responses through differential regulation of IL-12 and IL-10 cytokine gene expression in macrophages. Although Opn has been suggested to play a role in the development of type-1 immunity, little is known about control of Opn gene expression. Here, we report that Opn gene expression in activated T cells, but not macrophages, is regulated by T-bet, a transcription factor that controls CD4 ؉ T helper (Th1) cell lineage commitment. We also find that T-bet-dependent expression of Opn in T cells is essential for efficient skewing of CD4 ؉ T and CD8 ؉ T cells toward the Th1 and type 1 CD8 ؉ T cells (Tc1) pathway, respectively. Taken together, these findings begin to delineate the genetic basis of Opn expression in T cells and further clarify the role of Opn in Th and Tc1 development.genetic programming ͉ T helper 1 development ͉ type-1 immune response T he osteopontin (Opn) glycoprotein has been independently identified and studied by investigators from numerous scientific fields in view of its role in immune responses, vascularization, and bone formation through interactions with mononuclear, endothelial, and bone cells, respectively. Analysis of its contribution to immune responses has suggested that Opn expression can set the stage for protective type-1 immune responses after viral and bacterial infection through differential regulation of IL-12 and IL-10 cytokine production (1-3).Studies of Opn-deficient (Opn Ϫ/Ϫ ) mice have indicated that Opn contributes to host resistance against diverse microbial pathogens including herpes simplex virus 1, Listeria monocytogenes (4), and rotavirus (5). Opn expression is also essential for effective Th1-dependent granuloma formation and a positive clinical outcome in patients suffering from mycobacterial infection (6), whereas ectopic Opn expression has been implicated in the granulomatous lesions of Crohn's disease (7). Dysregulated Opn expression has also been implicated in several autoimmune disorders, including murine experimental autoimmune encephalomyelitis (EAE) (8, 9), multiple sclerosis (10), rheumatoid arthritis (11), and atherosclerosis (12, 13). Dysregulated Opn expression has been correlated with excessive Th1 polarization of CD4 ϩ T cells in these disorders (7,14) opening the possibility that Opn gene expression may directly contribute to Th1͞type 1 CD8 ϩ T cells (Tc1) genetic programming. However, the genetic basis of Opn expression in Th-cell subsets is not well understood.T-bet, a member of the T box family of transcription factors, is the master coordinator of gene expression in T cells that initiate type-1 immunity and is essential for Th1 cell polarization (15). Thus, T-bet deficiency reduces IFN-␥ production by activated CD4 ϩ T cells and T cell antigen receptor (TCR)-transgenic CD8...

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

“…Although how the signaling events interacting each other to depress the transcription of OPN and IL-17 still needs to be explored, this finding complements the IFN-b/DC/Th17 theory by showing direct regulation of OPN and IL-17 production in CD4 1 T cells. In addition, the activation of STAT1 by IFNAR signaling in CD4 1 T cells [14,30,31,[48][49][50]. In these studies, reduced T-cell proliferation in response to the eliciting antigen and altered cytokine profile of autoreactive T cells confirm the role of OPN in the disease processes [14,49].…”

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

“…First, the expression of OPN is mediated by T-bet, which is indispensable for the polarization of Th1 immune response (Shinohara et al 2005). The secreted OPN further affects the expression of IL-12 (enhancement) and IL-10 (inhibition) that favors Th1-deviation (Ashkar et al 2000).…”

Osteopontin: Role in immune regulation and stress responses

“…Moreover, soluble OPN may modulate the differentiation and proliferation of CD4 + and CD8 + T cells (Higuchi et al, 2004). Shinohara et al (2005) Recent evidence indicates that plasma OPN levels increase in active Crohn's disease compared with quiescent disease and decline after treatment with the anti-TNF-α monoclonal antibody infliximab (Agnholt et al, 2007). Furthermore, OPN regulates cell-mediated immunity by promoting T cell proliferation and migration as demonstrated in transgenic mice over-expressing OPN; these mice also exhibited an increase in the percentage of CD4 + T cells in lymph nodes (Higuchi et al, 2004).…”

“…OPN has been identified as a major factor in the regulation of immune responses and inflammation; its expression is up-regulated in activated T cells, macrophages and NK cells Shinohara et al, 2005). It is classified as a Th1 cytokine because it enhances production of the Th1 cytokines IFN-γ and IL-12 and inhibits production of the Th2 cytokine IL-10 by macrophages (Ashkar et al, 2000;Renkl et al, 2005).…”