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Cutting Edge: Ikaros Null Thymocytes Mature into the CD4 Lineage with Reduced TCR Signal: A Study Using CD3 Immunoreceptor Tyrosine-Based Activation Motif Transgenic Mice¹

Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Positive selection is a critical T cell developmental checkpoint that is driven by TCR signals. Enhanced positive selection toward the CD4 lineage occurs in the absence of Ikaros. One explanation for this phenotype is that Ikaros establishes the TCR signaling threshold that must be overcome for positive selection to occur. In the current study, this possibility is explored through the use of CD3 ITAM transgenic mice that express a CD3 -chain with zero, one, or three ITAMs and an MHC class II (DO11.10)- or MHC class I (H-Y)-restricted TCR transgene. Using this system, we demonstrate that in the absence of Ikaros, thymocytes are able to mature into the CD4 lineage with reduced TCR signaling potential compared with that required to drive the maturation of wild-type thymocytes. We also demonstrate that maturation into the CD8 lineage is enhanced under conditions of reduced TCR signaling potential in the absence of Ikaros.

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 by American Heart Association Grant 0650111Z and National Institutes of Health Grant R01 CA104962-01A1 (to S.W.). J.A.U. was supported by Public Health Service Grant 5 T32 AI07476-08.

² J.A.U. and W.B. contributed equally to this work.

³ Current address: Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.

⁴ Address correspondence and reprint requests to Dr. Susan Winandy, Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Morton 6-654, Chicago, IL 60611. E-mail address: s-winandy{at}northwestern.edu

⁵ Abbreviations used in this paper: DP, double positive, CD40L, CD40 ligand; IK, Ikaros; qRT-PCR, quantitative RT-PCR; SP, single positive; Tg, transgene/transgenic.

⁶ The online version of this article contains supplemental material.

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