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

摘要

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 decarboxylase_(65) 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#alpha# loops than their Th1 counterparts. This trend was confirmed by analyzing TCR#alpha# transcripts of Th1 and Th2 polarized, bulk populations. Molecular modeling of Th1- and Th2-derived TCRs demonstrated that Th2 CDR3#alpha# comprised larger side chain residues than Th1 TCRs. The elongated, bulky Th2 CDR3#alpha# 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 tat CD4~+ T cells selected from the available repertoire under T2 polarizing conditions tend to have elongated TCR CDR3#alpha# loops predicted to alter TCR binding, reducing contact at other interfaces and potentially leading to impeded TCR triggering.