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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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Functional characteristics of Tax11-19–specific T cell clones on the recognition of cognate MHC/peptide ligand and their TCR Vβ chain usage. EBV-transformed B cells expressing HLA-A*0201 incubated either with or without 50 μM Tax11-19 peptide were used as target cells or APCs. The 51Cr release assay was performed using 10:1 E/T ratio for the cytotoxic activity. Proliferative activity was assessed by [3H]thymidine incorporation. IFN-γ and IL-4 were measured from culture supernatants by capture ELISA after 48 h of incubation and the detection limits were 100 and 10 pg/ml for IFN-γ and IL-4, respectively. TCR Vβ chain usage was determined by indirect immunofluorescence staining using specific mAb.
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fig1: Functional characteristics of Tax11-19–specific T cell clones on the recognition of cognate MHC/peptide ligand and their TCR Vβ chain usage. EBV-transformed B cells expressing HLA-A*0201 incubated either with or without 50 μM Tax11-19 peptide were used as target cells or APCs. The 51Cr release assay was performed using 10:1 E/T ratio for the cytotoxic activity. Proliferative activity was assessed by [3H]thymidine incorporation. IFN-γ and IL-4 were measured from culture supernatants by capture ELISA after 48 h of incubation and the detection limits were 100 and 10 pg/ml for IFN-γ and IL-4, respectively. TCR Vβ chain usage was determined by indirect immunofluorescence staining using specific mAb.

Mentions: Using an HLA-A2/Tax11-19 tetramer for the selection and expansion of antigen-specific CD8+ T cells, we generated a diverse clonal population of CD8+ T cells reactive to Tax11-19 from the peripheral blood of an HLA-A*0201–expressing patient with HTLV-1–associated myelopathy (17). Five representative T cell clones established by this method and one T cell clone established previously by repeated antigenic stimulation were used in this work (18). The functional activities of these clones on the stimulation with cognate MHC/Ag (HLA-A*0201–Tax11-19) were examined and summarized in Fig. 1. As expected, all of the T cell clones exhibited a high degree of cytotoxic activity accompanied by secretion of >1 ng/ml of IFN-γ in an antigen-specific fashion, whereas variable amounts of proliferation and IL-4 secretion were observed among different T cell clones (Fig. 1).


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)

Functional characteristics of Tax11-19–specific T cell clones on the recognition of cognate MHC/peptide ligand and their TCR Vβ chain usage. EBV-transformed B cells expressing HLA-A*0201 incubated either with or without 50 μM Tax11-19 peptide were used as target cells or APCs. The 51Cr release assay was performed using 10:1 E/T ratio for the cytotoxic activity. Proliferative activity was assessed by [3H]thymidine incorporation. IFN-γ and IL-4 were measured from culture supernatants by capture ELISA after 48 h of incubation and the detection limits were 100 and 10 pg/ml for IFN-γ and IL-4, respectively. TCR Vβ chain usage was determined by indirect immunofluorescence staining using specific mAb.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Functional characteristics of Tax11-19–specific T cell clones on the recognition of cognate MHC/peptide ligand and their TCR Vβ chain usage. EBV-transformed B cells expressing HLA-A*0201 incubated either with or without 50 μM Tax11-19 peptide were used as target cells or APCs. The 51Cr release assay was performed using 10:1 E/T ratio for the cytotoxic activity. Proliferative activity was assessed by [3H]thymidine incorporation. IFN-γ and IL-4 were measured from culture supernatants by capture ELISA after 48 h of incubation and the detection limits were 100 and 10 pg/ml for IFN-γ and IL-4, respectively. TCR Vβ chain usage was determined by indirect immunofluorescence staining using specific mAb.
Mentions: Using an HLA-A2/Tax11-19 tetramer for the selection and expansion of antigen-specific CD8+ T cells, we generated a diverse clonal population of CD8+ T cells reactive to Tax11-19 from the peripheral blood of an HLA-A*0201–expressing patient with HTLV-1–associated myelopathy (17). Five representative T cell clones established by this method and one T cell clone established previously by repeated antigenic stimulation were used in this work (18). The functional activities of these clones on the stimulation with cognate MHC/Ag (HLA-A*0201–Tax11-19) were examined and summarized in Fig. 1. As expected, all of the T cell clones exhibited a high degree of cytotoxic activity accompanied by secretion of >1 ng/ml of IFN-γ in an antigen-specific fashion, whereas variable amounts of proliferation and IL-4 secretion were observed among different T cell clones (Fig. 1).

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