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CD4 T Cells Selected by Antigen Under Th2 Polarizing Conditions Favor an Elongated TCR Chain Complementarity-Determining Region 3

Rosemary J. Boyton^*, Nathan Zaccai, E. Yvonne Jones and Daniel M. Altmann^2,*,

^* Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, and Human Disease Immunogenetics Group, Department of Infectious Diseases, Imperial College School of Science, Technology, and Medicine, Hammersmith Hospital, London, United Kingdom; and Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

The affinity of the MHC/peptide/TCR interaction is thought to be one factor determining the differentiation of CD4⁺ T cells into Th1 or Th2 phenotypes. To study whether CD4⁺ cells generated under conditions favoring Th1 or Th2 responses select structurally different TCRs, Th1 and Th2 clones and lines were generated from nonobese diabetic and nonobese diabetic H2-E transgenic mice against the peptides proteolipoprotein 56–70, glutamic acid decarboxylase₆₅ 524–543, and heat shock protein-60 peptides 168–186 and 248–264. Th1/Th2 polarization allowed the generation of clones and lines with fixed peptide specificity and class II restriction but differing in Th1/Th2 phenotype in which the impact on TCR selection and structure could be studied. The Th2 clones tended to use longer TCR complementarity-determining region (CDR)3 loops than their Th1 counterparts. This trend was confirmed by analyzing TCR transcripts from Th1 and Th2 polarized, bulk populations. Molecular modeling of Th1- and Th2-derived TCRs demonstrated that Th2 CDR3 comprised larger side chain residues than Th1 TCRs. The elongated, bulky Th2 CDR3 loops may be accommodated at the expense of less optimal interactions between the MHC class II/peptide and other CDR loops of the TCR. We propose that CD4⁺ T cells selected from the available repertoire under Th2 polarizing conditions tend to have elongated TCR CDR3 loops predicted to alter TCR binding, reducing contact at other interfaces and potentially leading to impeded TCR triggering.

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