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The Activation Threshold of CD4⁺ T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla¹

Tom Li Stephen,^* Anastasia Tikhonova,^* Janice M. Riberdy, and Terri M. Laufer^2*

^*Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; St. Jude Children’s Research Hospital, Memphis, TN 38105; and Department of Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4⁺ single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4⁺ T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.

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 National Institutes of Health Grant R01 AI068819 (to T.M.L.) and an Arthritis Foundation postdoctoral fellowship (to T.L.S.).

² Address correspondence and reprint requests to Dr. Terri M. Laufer, Department of Medicine, University of Pennsylvania, 753 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail address: tlaufer{at}mail.med.upenn.edu

³ Abbreviations used in this paper: SP, single positive; APL, altered peptide ligand; BM, bone marrow; BMC, BM chimera; DC, dendritic cell; DP, double positive; inter, intermediate; MHC II, MHC class II; mTEC, medullary thymic epithelial cell; MUT, mutant; PCC, pigeon cytochrome c; ppERK, diphosphorylated ERK; SHP-1, Src homology region 2 domain-containing phosphatase 1; Tg, transgenic; WT, wild type.

⁴ The online version of this article contains supplemental material.