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* University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232;
Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany; and
Department of Medicine and
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
Objective: Interaction of ICOS with its ligand (ICOSL, B7-H2) promotes T cell responses. As CD4+CD25highFoxp3+ naturally occurring T regulatory cells in melanoma patients express ICOS, we investigated the impact of ICOS on naturally occurring T regulatory cell function. Methods: Expression of ICOS and T regulatory (Treg) cell markers was determined on CD4+CD25high T cells in PBMC and tumor-infiltrating lymphocytes from melanoma patients (n = 10) and PBMC of normal controls (n = 10) by multicolor flow cytometry. Suppression mediated by sorted ICOShigh and ICOSlow Treg was assessed in CFSE-based suppression assays with autologous CD4+CD25– responder cells (RC). Transwell inserts separating Treg from RC were used to evaluate suppression mechanisms used by Treg. ICOShigh or ICOSlow Treg were coincubated with RC ± TCR and IL-2 stimulation. ICOShigh and ICOS– Treg were also expanded under conditions previously shown to induce Tr1 from RC. Results: Treg in tumor-infiltrating lymphocytes expressed ICOS (mean fluorescence intensity = 70 ± 10), while Treg in PBMC had low ICOS expression (mean fluorescence intensity = 3.5 ± 2.5, p 
0.001). ICOShigh Treg up-regulated Treg markers (p 0.0016) and mediated stronger suppression (p 0.001) relative to ICOSlow Treg. ICOShigh Treg induced Tr1 cells in nonactivated RC and Th2 cells in preactivated RC. ICOShigh Treg exposed to Tr1 cytokines expressed IL-10 and suppressed RC (92 ± 12%) in contrast to ICOSlow Treg, which mediated low suppression (21 ± 15%; p 0.0028). Conclusion: ICOShigh Treg can induce diverse immune responses in RC, depending on activation signals and cytokines present. ICOShigh Treg induce Tr1 or Th2 cells depending on the activation state of RC. In a "Tr1" cytokine milieu, ICOShigh Treg transit to Tr1.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants R01 DE13918, P01 DE12321, and P01CA109688 (to T.L.W.), and by Philip Morris USA Inc. and Philip Morris International (to C.B., S.L., and T.L.W.).
2 L.S. and C.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213. E-mail address: whitesidetl{at}upmc.edu
4 Abbreviations used in this paper: ICOSL, ICOS ligand; nTreg, naturally occurring T regulatory; TA, tumor Ag; TIL, tumor-infiltrating lymphocytes; NC, normal control; RC, responder cell; sTGF-β1, surface-bound TGF-β1; int, intermediate; MFI, mean fluorescence intensity; SCS, single-cell sorted (or sorting); TR, transwell insert; SN, supernatant; mag, magnification; GITR, glucocorticoid-induced TNF receptor; i, intracellular; IVA, in vitro activated.
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