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Molecular Requirements for T Cell Recognition by a Major Histocompatibility Complex Class II–restricted T Cell Receptor: The Involvement of the Fourth Hypervariable Loop of the V Domain

From the Center for Immunology and Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8576

The role of two central residues (K68, E69) of the fourth hypervariable loop of the V domain (HV4) in antigen recognition by an MHC class II–restricted T cell receptor (TCR) has been analyzed. The TCR recognizes the NH₂-terminal peptide of myelin basic protein (Ac1-11, acetylated at NH₂ terminus) associated with the class II MHC molecule I-A^u. Lysine 68 (K68) and glutamic acid 69 (E69) of HV4 have been mutated both individually and simultaneously to alanine (K68A, E69A). The responsiveness of transfectants bearing wild-type and mutated TCRs to Ac1-11–I-A^u complexes has been analyzed in the presence and absence of expression of the coreceptor CD4. The data demonstrate that in the absence of CD4 expression, K68 plays a central role in antigen responsiveness. In contrast, the effect of mutating E69 to alanine is less marked. CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade. The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell–antigen-presenting cell interaction.

Key Words: T cell receptor • V domain • fourth hypervariable loop • antigen recognition • CD4 coreceptor

A. Qadri's present address is National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.

¹ Abbreviations used in this paper: APC, antigen-presenting cell; CD, circular dichroism; CDR, complementarity determining region; E69, glutamic acid 69; E69A, mutation of E69 to alanine; HV4, the fourth hypervariable loop of the V domain; ITAM, immune receptor tyrosine-based activation motif; K68, Lysine 68; K68A, mutation of K68 to alanine; MBP, myelin basic protein; PBS, phosphate-buffered saline; pMHC, peptide– major histocompatibility complex; TCR, T cell receptor.

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