Leukemia (2007) 21, 175–192 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu LETTERS TO THE EDITOR Enhanced CD28 signaling may be a common mechanism underlying resistance to regulation Leukemia (2007) 21, 175. doi:10.1038/sj.leu.2404453; published online 16 November 2006 We would like to point out a reference conspicuously omitted in an Original Article published online on 17 August 2006. In this article, Loskog et al.1 report that the expression of a chimeric receptor that includes the intracellular portion of the CD28 receptor fused to the z-chain and CD19 single-chain Fv (CD19zCD28) resulted in the resistance to regulation by regulatory T cells in a model of tumor rejection. Additionally, this complex also led to a significant increase in the threshold of responsiveness to the immunosuppressive cytokine transforming growth factor-b (TGF-b). The authors describe that the increased signaling through the CD28 pathway leads to an increase in T cell proliferation, an independence to IL-2, and enhanced nuclear factor-kappa B (NF-kB) activation, which is dependent on phosphatidylinositol 3-kinase (PI3K) activation. We reported in both 2004 and 2006 that mice deficient in Cbl-b, which have been shown to develop multiorgan inflammatory disease, have T-cell receptor (TCR) activation that is CD28-independent, and have T cell hyperactivation of the PI3K-Akt pathway, demonstrate resistance to suppression by both CD4 þ CD25 þ regulatory T cells and TGF-b.2,3 We termed this phenomenon ‘resistance to regulation’ in our 2004 article.2,3 Along with our previously published papers, the present article by Loskog et al. confirms the possibility that the hyperactivation of the CD28 pathway leading to enhanced NF-kB activation through the PI3K-Akt pathway, present in both Cbl-b-deficient T cells and the transgenically engineered chimeric receptor (CD19zCD28), may result in resistance to suppression by regulatory T cells. Loskog et al. state, ‘our own data now suggest another potential mechanism of benefit, as the effects of CD28 activation via chimeric receptor ligation also extend to protection from Treg cells and the inhibitory cytokines they secrete’. We, in fact, demonstrated the relevance of this mechanism in CD28-independent Cbl-b-deficient T cells in a murine tumor model in our Journal of Immunology ‘Cutting Edge’ article in February of this year.3 Thus, this report by Loskog et al. confirms the results of our two prior publications showing that resistance to regulation may be related to enhanced CD28 signaling, yet these authors do not reference either of these publications. We believe this is a major oversight on the part of the authors. EA Wohlfert1,2 and RB Clark1,2 Department of Immunology, Center of Immunotherapy for Cancer and Infectious Diseases, Farmington, CT, USA and 2 Division of Rheumatic Diseases, Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA E-mail: rclark@nso2.uchc.edu 1 References 1 Loskog A, Giandomenico V, Rossig C, Dotti G, Brenner MK. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia (published online August 17, 2006; doi: 10.1038/sj.leu.2404366). 2 Wohlfert EA, Callahan MK, Clark RB. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b/ mice. J Immunol 2004; 173: 1059–1065. 3 Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB. Cutting Edge: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 2006; 176: 1316–1320. Reply to ‘Enhanced CD28 signaling may be a common mechanism underlying resistance to regulation’ by E Wohlfert and Clark RB 2 Baylor College of Medicine, Houston, TX, USA. E-mail: angelica.loskog@klinimm.uu.se Leukemia (2007) 21, 175. doi:10.1038/sj.leu.2404454; published online 16 November 2006 Wohlfert EA and Clark RB had interesting comments1 to our article ‘Addition of the CD28 signaling domain to chimeric T cell receptors enhances CTL activation and resistance to T regulatory cells’ that was published in Leukemia online on 17 August 2006.2 We agree it is of interest to observe related phenomena in other experimental systems and we welcome this additional validation. A Loskog1 and MK Brenner2 Clinical Immunology, Div/Uppsala University, Rudbeck Laboratory, Uppsala, Sweden and 1 References 1 Wohlfert EA, Clark RB. Enhanced CD28 signaling may be a common mechanism underlying resistance to regulation (Letter to the Editor). Leukemia 2006. 2 Loskog A, Giandomenico V, Rossig C, Pule M, Rooney CM, Dotti G et al. Addition of the CD28 signaling domain to chimeric T cell receptors enhances CTL activation and resistance to T regulatory cells. Leukemia. Advance online publication, 17 August 2006.