T Helper Cell-specific Regulation of Inducible Costimulator Expression via Distinct Mechanisms Mediated by T-bet and GATA-3

Abstract

Inducible costimulator (ICOS) expression is critical for T cellmediated immunity. We showed previously that T cell receptor and CD28 coengagement up-regulate ICOS expression in activated T cells via the induction of NFATc2. Here, we examined the regulation of ICOS expression by Th-specific transcription factors T-bet and GATA-3. Overexpression of T-bet or GATA-3 alone could enhance, and NFATc2 could further synergize with either of them to increase, icos transcription. Although T-bet acted on the icos promoter, GATA-3 operated via an icos 3-untranslated region element. Interestingly, NFATc2 was found to bind promiscuously the icos promoter in developing Th0, Th1, and Th2 cells but became selectively associated with T-bet at the promoter and with GATA-3 at the 3-untranslated region in fully differentiated Th1 and Th2 cells, respectively. Collectively, our results reveal a temporally evolving circuit in which the nonselectively expressed NFATc2 cooperates with Th-restricted T-bet or GATA-3 to direct transcription of a costimulatory gene via distinct regulatory elements in different Th cells undergoing differentiation.

Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)

“…Whereas in Th1 cells ICOS expression is upregulated by binding of NFATc2 and the Th1 associated transcription factor T-bet to the ICOS promoter, in Th2 cells, its expression is upregulated by interactions between NFATc2 and the Th2 associated transcription factor GATA-3 with the 3 0 UTR region of ICOS mRNA [4]. Furthermore, in the Treg lineage, binding of the Th2 associated transcription factor IRF4 to the ICOS promoter is associated with ICOS expression, although the role that IRF4 plays in regulating ICOS transcription in Th2 cells remains unknown [12].…”

“…After activation, ICOS is expressed on unpolarized CD4 + T cells, as well as on the Th1, Th2, Th17, Tfh, and Treg lineages [3][4][5][6]7 ]. ICOS expression can be regulated at the transcriptional level by signaling molecules activated downstream of TCR engagement and CD28 costimulation, including the Src kinase Fyn and the MAP kinase ERK [8,9].…”

Knockdown of T‐bet expression in Mart‐127–35‐specific T‐cell‐receptor‐engineered human CD4+ CD25− and CD8+ T cells attenuates effector function

“…Ectopic expression or small interfering RNA-mediated knockdown of either GATA-3 or T-bet can also affect polarization in mouse CD4 + T cells. 21 The transcription factor T-bet directs the Th1 lineage commitment and is required for IFN-c expression in naive CD4 + T cells but not CD8 + T cells. 22,23 In T-bet knockout mice, CD4…”

<i>ICOS</i> gene polymorphisms in B-cell chronic lymphocytic leukemia in the Polish population

“…After activation, ICOS is expressed on unpolarized CD4 + cells as well on Th1, Th2, Th17, and Treg subpopulations [8][9][10][11][12]. This co-stimulatory molecule binds the B-7-related protein B7RP-1 [13].…”