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Distinct recognition by two subsets of T cells of an MHC class II-peptide complex.

ABSTRACT: We examine here the nature of the differential recognition by CD4+ T cells of a single peptide from hen-egg white lysozyme (HEL) presented by I-A(k) class II MHC molecules. Two subsets of T cells (called A and B) interact with the same peptide, each in unique ways that reflect the nature of the complex of peptide and MHC. We show that the A and B set of T cells can be distinguished by their functional interaction with the three T cell receptor (TCR) contact residues of the bound peptide. The dominant peptide of HEL selected from processing is bound in a single register where a critical TCR contact residue is situated about the middle of the core segment of the peptide: all T cells establish functional contact with it. Three sets of T cells, however, can be distinguished by their differential recognition of two TCR contacts situated at the amino and carboxyl sides of the central TCR contact residue. Type A T cells, the conventional cells that see the peptide after processing of HEL, need to recognize all three TCR contact residues. In contrast, the type B T cells recognize the peptide given exogenously, but not when processed: these T cells recognize either one of the peripheral TCR contact residues, indicating a much more flexible interaction of peptide with I-A(k) molecules. We discuss the mode of generation of the various T cells and their biological relevance.

SUBMITTER: Pu Z

PROVIDER: S-EPMC124386 | biostudies-literature | 2002 Jun

REPOSITORIES: biostudies-literature

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Distinct recognition by two subsets of T cells of an MHC class II-peptide complex.

Pu Zheng Z Carrero Javier A JA Unanue Emil R ER

Proceedings of the National Academy of Sciences of the United States of America 20020601 13

We examine here the nature of the differential recognition by CD4+ T cells of a single peptide from hen-egg white lysozyme (HEL) presented by I-A(k) class II MHC molecules. Two subsets of T cells (called A and B) interact with the same peptide, each in unique ways that reflect the nature of the complex of peptide and MHC. We show that the A and B set of T cells can be distinguished by their functional interaction with the three T cell receptor (TCR) contact residues of the bound peptide. The dom ...[more]

PMID: 12084929

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Project description:A primary initiating epitope in the NOD mouse model of Type 1 Diabetes (T1D) lies between residues 9 and 23 of the insulin B chain. The B:9-23 peptide can bind to the NOD MHC class II molecule (I-Ag7) in multiple registers, but only one, (register 3, R3), creates complexes able to stimulate the majority of pathogenic B:9-23-specific CD4+ T cells. Previously we generated a monoclonal antibody (mAb287) that targets this critical I-Ag7-B:9-23(R3) complex. When given weekly to pre-diabetic mice at either early or late stages of disease, mAb287 was able to delay or prevent T1D in the treated animals. Although the precise mechanism of action of mAb287 remains unclear, we hypothesized that it may involve deletion of antigen presenting cells (APCs) bearing the pathogenic IAg7-B:9-23(R3) complexes, and that this process might be rendered more efficient by re-directing cytotoxic T cells using a mAb287 chimeric antigen receptor (287-CAR). As anticipated, 287-CAR T cells secreted IFN-? in response to stimulation by I-Ag7-B:9-23(R3) complexes expressed on artificial APCs, but not I-Ag7 loaded with other peptides, and killed the presenting cells in vitro. A single infusion of 287-CAR CD8+ T cells to young (5 week old) NOD mice significantly delayed the onset of overt hyperglycemia compared to untreated animals (p?=?0.022). None of the 287-CAR CD8+ T cell treated mice developed diabetes before 18 weeks of age, while 29% of control-CAR T cell treated mice (p?=?0.044) and 52% of the un-treated mice (p?=?0.0001) had developed T1D by this time. However, the protection provided by 287-CAR CD8+ T cells declined with time, and no significant difference in overall incidence by 30 weeks between the 3 groups was observed. Mechanistic studies indicated that the adoptively transferred 287-CAR T cells selectively homed to pancreatic lymph nodes, and in some animals could persist for at least 1-2 weeks post-transfer, but were essentially undetectable 10-15 weeks later. Our study demonstrates that CAR T cells specific for a pathogenic MHC class II:peptide complex can be effective in vivo, but that a single infusion of the current iteration can only delay, but not prevent, the development of T1D. Future studies should therefore be directed towards optimizing strategies designed to improve the longevity of the transferred cells.

Dataset Information

Distinct recognition by two subsets of T cells of an MHC class II-peptide complex.

Publications

Distinct recognition by two subsets of T cells of an MHC class II-peptide complex.

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