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Allelic variation of MHC structure alters peptide ligands to induce atypical partial agonistic CD8+ T cell function.

Lim DG, Slavik JM, Bourcier K, Smith KJ, Hafler DA - J. Exp. Med. (2003)

Bottom Line: Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs).Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression.These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115-5817, USA.

ABSTRACT
T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2-Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC-peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.

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Location of HLA-A2 subtype polymorphic residues. (a and b) The HLA-A2–Tax11-19 complex viewed from above the peptide binding groove. The positions of the HLA-A2 subtype polymorphic residues shown in Table I are marked on the MHC. Residue 9, dark blue; residue 43, green; residue 95, red; residue 149, cyan; residue 152, yellow; and residue 156, magenta. The peptide is shown in yellow. (c and d) The HLA-A2–Tax11-19 complex viewed from within the peptide-binding groove. The peptide is shown in yellow and the MHC is in blue. (c) The location of polymorphic residue 156 in the D-pocket. (d) The location of polymorphic residue 95 in the F-pocket. a, c, and d were drawn using RIBBONS (44); b was generated with Grasp (45).
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fig4: Location of HLA-A2 subtype polymorphic residues. (a and b) The HLA-A2–Tax11-19 complex viewed from above the peptide binding groove. The positions of the HLA-A2 subtype polymorphic residues shown in Table I are marked on the MHC. Residue 9, dark blue; residue 43, green; residue 95, red; residue 149, cyan; residue 152, yellow; and residue 156, magenta. The peptide is shown in yellow. (c and d) The HLA-A2–Tax11-19 complex viewed from within the peptide-binding groove. The peptide is shown in yellow and the MHC is in blue. (c) The location of polymorphic residue 156 in the D-pocket. (d) The location of polymorphic residue 95 in the F-pocket. a, c, and d were drawn using RIBBONS (44); b was generated with Grasp (45).

Mentions: As shown in Fig. 4 (a and b), the amino acid residue at position 9 of HLA-A2 is located in the B-pocket of groove. However, this position alone is unlikely to affect the TCR recognition of Tax11-19 because all of the T cell clones showed similar recognition pattern to both A*0201 and A*0206, which have identical amino acid sequence except for this position. The amino acid residue at position 43 of HLA-A2 is located in a loop connecting β sheets, not in the vicinity of peptide or TCR (Fig. 4, a and b), so this position is unlikely to have an effect on TCR recognition. The amino acid residue 95 is situated at the base of the groove (F-pocket), but is not in direct Van der Waals contact with the peptide (Fig. 4, a and d). A polymorphism at this position could have an indirect effect on bound peptide structure, although the conservative Val to Leu substitution at this position is unlikely to have a dramatic affect on the conformation of the bound peptide. Finally, residue 156 is within the Van der Waals radius of the P3 side chain of the Tax peptide (Fig. 4 c), so the substitution of Leu to a bulky Trp is more likely to affect the structure of the peptide bound in the MHC molecule and, thus, indirectly affect TCR recognition. This analysis demonstrates that polymorphic amino acids in the peptide binding site of HLA-A2 molecule, particularly residue 156, are likely to affect functional activity of T cell clones.


Allelic variation of MHC structure alters peptide ligands to induce atypical partial agonistic CD8+ T cell function.

Lim DG, Slavik JM, Bourcier K, Smith KJ, Hafler DA - J. Exp. Med. (2003)

Location of HLA-A2 subtype polymorphic residues. (a and b) The HLA-A2–Tax11-19 complex viewed from above the peptide binding groove. The positions of the HLA-A2 subtype polymorphic residues shown in Table I are marked on the MHC. Residue 9, dark blue; residue 43, green; residue 95, red; residue 149, cyan; residue 152, yellow; and residue 156, magenta. The peptide is shown in yellow. (c and d) The HLA-A2–Tax11-19 complex viewed from within the peptide-binding groove. The peptide is shown in yellow and the MHC is in blue. (c) The location of polymorphic residue 156 in the D-pocket. (d) The location of polymorphic residue 95 in the F-pocket. a, c, and d were drawn using RIBBONS (44); b was generated with Grasp (45).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196091&req=5

fig4: Location of HLA-A2 subtype polymorphic residues. (a and b) The HLA-A2–Tax11-19 complex viewed from above the peptide binding groove. The positions of the HLA-A2 subtype polymorphic residues shown in Table I are marked on the MHC. Residue 9, dark blue; residue 43, green; residue 95, red; residue 149, cyan; residue 152, yellow; and residue 156, magenta. The peptide is shown in yellow. (c and d) The HLA-A2–Tax11-19 complex viewed from within the peptide-binding groove. The peptide is shown in yellow and the MHC is in blue. (c) The location of polymorphic residue 156 in the D-pocket. (d) The location of polymorphic residue 95 in the F-pocket. a, c, and d were drawn using RIBBONS (44); b was generated with Grasp (45).
Mentions: As shown in Fig. 4 (a and b), the amino acid residue at position 9 of HLA-A2 is located in the B-pocket of groove. However, this position alone is unlikely to affect the TCR recognition of Tax11-19 because all of the T cell clones showed similar recognition pattern to both A*0201 and A*0206, which have identical amino acid sequence except for this position. The amino acid residue at position 43 of HLA-A2 is located in a loop connecting β sheets, not in the vicinity of peptide or TCR (Fig. 4, a and b), so this position is unlikely to have an effect on TCR recognition. The amino acid residue 95 is situated at the base of the groove (F-pocket), but is not in direct Van der Waals contact with the peptide (Fig. 4, a and d). A polymorphism at this position could have an indirect effect on bound peptide structure, although the conservative Val to Leu substitution at this position is unlikely to have a dramatic affect on the conformation of the bound peptide. Finally, residue 156 is within the Van der Waals radius of the P3 side chain of the Tax peptide (Fig. 4 c), so the substitution of Leu to a bulky Trp is more likely to affect the structure of the peptide bound in the MHC molecule and, thus, indirectly affect TCR recognition. This analysis demonstrates that polymorphic amino acids in the peptide binding site of HLA-A2 molecule, particularly residue 156, are likely to affect functional activity of T cell clones.

Bottom Line: Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs).Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression.These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115-5817, USA.

ABSTRACT
T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2-Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC-peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.

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