HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vignali, D. A. A. Articles by Vignali, K. M. Search for Related Content PubMed PubMed Citation Articles by Vignali, D. A. A. Articles by Vignali, K. M.

Profound Enhancement of T Cell Activation Mediated by the Interaction Between the TCR and the D3 Domain of CD4¹

Dario A. A. Vignali^2,*, and Kate M. Vignali^*

^* Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38101; and Department of Pathology, University of Tennessee Medical Center, Memphis, TN 38163

CD4 plays an important role in the activation and development of CD4⁺ T cells. This is mediated via its bivalent interaction with MHC class II molecules and the TCR:CD3 complex through p56^lck. Recent studies have implicated a third site of interaction between the membrane-proximal extracellular domains of CD4 and the TCR. Due to these multiple interactions, direct evidence for the functional importance of this extracellular association has remained elusive. Furthermore, the residues that mediate this interaction are unknown. In this study, we analyzed the function of 61 CD4 mutants. Alanine substitution of just 2 residues, either Q114/F182 or F182/F201, which are partially buried and located close to the D2/D3 interface, completely abrogated CD4 function. Direct evidence for the functional importance of TCR:CD4.D3 interaction was obtained using an anti-CD3fos:anti-CD4jun-bispecific Ab. Surprisingly, it induced strong T cell activation in hybridomas transfected with cytoplasmic-tailless CD4, despite the lack of association with either p56^lck or MHC class II molecules. However, this effect was completely abrogated with the CD4 mutants Q114A/F182A or F182A/F201A. These data demonstrate that TCR:CD4.D3 interaction can have a profound effect on T cell activation and obviates the need for receptor oligomerization.

This article has been cited by other articles:

				A. Maekawa, B. Schmidt, B. Fazekas de St. Groth, Y.-H. Sanejouand, and P. J. Hogg Evidence for a Domain-Swapped CD4 Dimer as the Coreceptor for Binding to Class II MHC. J. Immunol., June 1, 2006; 176(11): 6873 - 6878. [Abstract] [Full Text] [PDF]

				A. L. Szymczak and D. A. A. Vignali Plasticity and Rigidity in Adaptor Protein-2-Mediated Internalization of the TCR:CD3 Complex J. Immunol., April 1, 2005; 174(7): 4153 - 4160. [Abstract] [Full Text] [PDF]

				C. J. Workman and D. A. A. Vignali Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223) J. Immunol., January 15, 2005; 174(2): 688 - 695. [Abstract] [Full Text] [PDF]

				N. L. La Gruta, H. Liu, S. Dilioglou, M. Rhodes, D. L. Wiest, and D. A. A. Vignali Architectural Changes in the TCR:CD3 Complex Induced by MHC:Peptide Ligation J. Immunol., March 15, 2004; 172(6): 3662 - 3669. [Abstract] [Full Text] [PDF]

				C. J. Workman, K. J. Dugger, and D. A. A. Vignali Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3 J. Immunol., November 15, 2002; 169(10): 5392 - 5395. [Abstract] [Full Text] [PDF]

				Y. Xiong, P. Kern, H.-C. Chang, and E. L. Reinherz T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4 J. Biol. Chem., February 16, 2001; 276(8): 5659 - 5667. [Abstract] [Full Text] [PDF]