Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes.
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.
Auphan-Anezin
Nathalie
N
Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite de la Méditerranée, Campus de Luminy, Marseille, France. auphan@ciml.univ-mrs.fr
Mazza
Catherine
C
Guimezanes
Annick
A
Barrett-Wilt
Gregory A
GA
Montero-Julian
Felix
F
Roussel
Alain
A
Hunt
Donald F
DF
Malissen
Bernard
B
Schmitt-Verhulst
Anne-Marie
AM
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells; D006183:H-2 Antigens / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D007519:Isoantigens / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D006649:Histocompatibility Antigens; D007519:Isoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell