Article

Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes.

Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite de la Méditerranée, Campus de Luminy, Marseille, France.
European Journal of Immunology (Impact Factor: 4.52). 08/2006; 36(7):1856-66. DOI: 10.1002/eji.200635895
Source: PubMed

ABSTRACT We have characterized three different programs of activation for alloreactive CD8 T cells expressing the BM3.3 TCR, their elicitation depending on the characteristics of the stimulating peptide/MHC complex. The high-affinity interaction between the TCR and the K(b)-associated endogenous peptide pBM1 (INFDFNTI) induced a complete differentiation program into effector cells correlated with sustained ERK activation. The K(bm8) variant elicited a partial activation program with delayed T cell proliferation, poor CTL activity and undetectable ERK phosphorylation; this resulted from a low-avidity interaction of TCR BM3.3 with a newly identified endogenous peptide, pBM8 (SQYYYNSL). Interestingly, mismatched pBM1/K(bm8) complexes induced a split response in BM3.3 T cells, with total reconstitution of T cell proliferation but defective generation of CTL activity that was correlated with strong but shortened ERK phosphorylation. Crystal structures highlight the molecular basis for the higher stability of pBM8/K(bm8) compared to pBM1/K(bm8) complexes that exist in two conformers. This study illustrates the importance of the stability of both peptide/MHC and peptide/MHC-TCR interactions for induction of sustained signaling required to induce optimal CTL effector functions. Subtle allelic structural variations, amplified by peptide selection, may thus orient distinct outcomes of alloreactive TCR-based therapies.

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Available from: Nathalie Auphan-Anezin, Jul 10, 2015
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    • "identification of the endogenous peptide (pBM8: SQYYYNSL) recognized by the BM3.3 TCR in the context of H-2K bm8 showed that its anchor residues differed from the ones found in pBM1 and VSV8 sequences (Auphan-Anezin et al, 2006). Moreover, further comparison of the pBM8 sequence with that of pBM1 (INFDFNTI) and VSV8 (RGYVYQGL) revealed a single homologous TCR-exposed residue at P6. "
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