The T cell receptor's alpha-chain connecting peptide motif promotes close approximation of the CD8 coreceptor allowing efficient signal initiation.
The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The alpha-chain connecting peptide motif (alpha-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR alpha-chain. TCRs lacking the alpha-CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant alpha-CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the alpha-CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCR-CD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the alpha-CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.
Laboratory of Transplantation Immunology and Nephrology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Michel
M
Mallaun
Dieter
D
Naeher
Mark A
MA
Daniels
Pia P
PP
Yachi
Barbara
B
Hausmann
Immanuel F
IF
Luescher
Nicholas R J
NR
Gascoigne
Ed
E
Palmer
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D016827:CD8 Antigens / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D006801:Humans; D006825:Hybridomas; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C433839:CD8alphabeta antigen; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta