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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.

Show MeSH
Phospho-MAPKs are not induced but phospho-c-Jun is slowly induced and sustained in TP60 T cells after stimulation with Tax11-19–HLA-A*0205. TP60 T cells were cocultured with LCLs prepulsed with 10 μM of indicated peptides. After incubation for the indicated times, cells were fixed and intracellularly stained for phospho-MAPKs and c-Jun. Expression levels of phospho-MAPKs and c-Jun were analyzed in T cells with the exclusion of LCLs as described in Materials and Methods. One representative experiment of four is shown.
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fig7: Phospho-MAPKs are not induced but phospho-c-Jun is slowly induced and sustained in TP60 T cells after stimulation with Tax11-19–HLA-A*0205. TP60 T cells were cocultured with LCLs prepulsed with 10 μM of indicated peptides. After incubation for the indicated times, cells were fixed and intracellularly stained for phospho-MAPKs and c-Jun. Expression levels of phospho-MAPKs and c-Jun were analyzed in T cells with the exclusion of LCLs as described in Materials and Methods. One representative experiment of four is shown.

Mentions: Another major signaling pathway in T cell activation is the Ras–MAPK pathway (32). When we examined phosphorylated MAP kinases, including ERK1/2, p38 MAPK, and JNK, we could not detect the activation of these kinase pathways after stimulation with Tax11-19–HLA-A*0205 (Fig. 7). However, a high amount of phosphorylated c-Jun (described previously as one of the signaling intermediates; reference 33) was detected for a prolonged time period, up to 42 h after stimulation with Tax11-19–HLA-A*0205 with delayed kinetics even though upstream active kinase, pJNK, could not be detected at any time points (Fig. 7). In contrast, a higher amount of p-c-Jun was induced initially but reverted to background levels within 18 h after stimulation with a classical form of APL, F3R/HLA-A*0201 (Fig. 7). In total, these data demonstrate that Tax11-19–HLA-A*0205 cannot trigger TP60 TCR strongly enough to induce early signaling cascades, but can induce the accumulation of signaling intermediates by trickle through the weak early activation cascade.


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)

Phospho-MAPKs are not induced but phospho-c-Jun is slowly induced and sustained in TP60 T cells after stimulation with Tax11-19–HLA-A*0205. TP60 T cells were cocultured with LCLs prepulsed with 10 μM of indicated peptides. After incubation for the indicated times, cells were fixed and intracellularly stained for phospho-MAPKs and c-Jun. Expression levels of phospho-MAPKs and c-Jun were analyzed in T cells with the exclusion of LCLs as described in Materials and Methods. One representative experiment of four is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196091&req=5

fig7: Phospho-MAPKs are not induced but phospho-c-Jun is slowly induced and sustained in TP60 T cells after stimulation with Tax11-19–HLA-A*0205. TP60 T cells were cocultured with LCLs prepulsed with 10 μM of indicated peptides. After incubation for the indicated times, cells were fixed and intracellularly stained for phospho-MAPKs and c-Jun. Expression levels of phospho-MAPKs and c-Jun were analyzed in T cells with the exclusion of LCLs as described in Materials and Methods. One representative experiment of four is shown.
Mentions: Another major signaling pathway in T cell activation is the Ras–MAPK pathway (32). When we examined phosphorylated MAP kinases, including ERK1/2, p38 MAPK, and JNK, we could not detect the activation of these kinase pathways after stimulation with Tax11-19–HLA-A*0205 (Fig. 7). However, a high amount of phosphorylated c-Jun (described previously as one of the signaling intermediates; reference 33) was detected for a prolonged time period, up to 42 h after stimulation with Tax11-19–HLA-A*0205 with delayed kinetics even though upstream active kinase, pJNK, could not be detected at any time points (Fig. 7). In contrast, a higher amount of p-c-Jun was induced initially but reverted to background levels within 18 h after stimulation with a classical form of APL, F3R/HLA-A*0201 (Fig. 7). In total, these data demonstrate that Tax11-19–HLA-A*0205 cannot trigger TP60 TCR strongly enough to induce early signaling cascades, but can induce the accumulation of signaling intermediates by trickle through the weak early activation cascade.

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.

Show MeSH