| First Author | Reynolds C | Year | 2014 |
| Journal | BMC Biol | Volume | 12 |
| Pages | 32 | PubMed ID | 24886643 |
| Mgi Jnum | J:224502 | Mgi Id | MGI:5662360 |
| Doi | 10.1186/1741-7007-12-32 | Citation | Reynolds C, et al. (2014) Elongated TCR alpha chain CDR3 favors an altered CD4 cytokine profile. BMC Biol 12:32 |
| abstractText | BACKGROUND: CD4 T lymphocyte activation requires T cell receptor (TCR) engagement by peptide/MHC (major histocompatibility complex) (pMHC). The TCR complementarity-determining region 3 (CDR3) contains variable alpha and beta loops critical for pMHC recognition. During any immune response, tuning of TCR usage through progressive clonal selection occurs. Th1 and Th2 cells operate at different avidities for activation and display distinct transcriptional programs, although polarization may be plastic, influenced by pathogens and cytokines. We therefore hypothesized that CDR3alphabeta sequence features may intrinsically influence CD4 phenotype during progression of a response. RESULTS: We show that CD4 polarization involves distinct CDR3alpha usage: Th1 and Th17 cells favored short TCR CDR3alpha sequences of 12 and 11 amino acids, respectively, while Th2 cells favored elongated CDR3alpha loops of 14 amino acids, with lower predicted affinity. The dominant Th2- and Th1-derived TCRalpha sequences with 14 amino acid CDR3 loops and 12 amino acid CDR3 loops, respectively, were expressed in TCR transgenics. The functional impact of these TCRalpha transgenes was assessed after in vivo priming with a peptide/adjuvant. The short, Th1-derived receptor transgenic T cell lines made IFNgamma, but not IL-4, 5 or 13, while the elongated, Th2-derived receptor transgenic T cell lines made little or no IFNgamma, but increased IL-4, 5 and 13 with progressive re-stimulations, mirrored by GATA-3 up-regulation. T cells from primed Th2 TCRalpha transgenics selected dominant TCR Vbeta expansions, allowing us to generate TCRalphabeta transgenics carrying the favored, Th2-derived receptor heterodimer. Primed T cells from TCRalphabeta transgenics made little or no IL-17 or IFNgamma, but favored IL-9 after priming with Complete Freund's adjuvant and IL-4, 5, 9, 10 and 13 after priming with incomplete Freund's. In tetramer-binding studies, this transgenic receptor showed low binding avidity for pMHC and polarized T cell lines show TCR avidity for Th17 > Th1 > Th2. While transgenic expression of a Th2-derived, 'elongated' TCR-CDR3alpha and the TCRalphabeta pair, clearly generated a program shifted away from Th1 immunity and with low binding avidity, cytokine-skewing could be over-ridden by altering peptide challenge dose. CONCLUSION: We propose that selection from responding clones with distinctive TCRs on the basis of functional avidity can direct a preference away from Th1 effector responses, favoring Th2 cytokines. |
