T cell selection and differential activation on structurally related HLA-DR4 ligands
J A Gebe1, E J Novak, W W Kwok
1Benaroya Research Institute, Virginia Mason Research Center, Seattle, WA 98101, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|September 7, 2001
Summary
T-cell receptor (TCR) cross-recognition allows T cells activated by one MHC molecule to respond to related ones, potentially causing aberrant immune responses in diseases like rheumatoid arthritis.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- T-cell receptor (TCR) interactions with MHC-peptide complexes exhibit plasticity, accommodating variations in ligands.
- This plasticity, known as TCR cross-recognition, can influence T cell responses and is relevant to autoimmune diseases.
- Rheumatoid arthritis is associated with specific HLA class II alleles, including DRB1*0401 and DRB1*0404.
Purpose of the Study:
- To investigate the role of TCR cross-recognition in T cell selection and activation.
- To analyze the relationship between TCR recognition of DRB1*0401 and DRB1*0404 HLA class II molecules.
- To explore the implications of TCR cross-recognition for autoimmune disease pathogenesis.
Main Methods:
- Utilized thymic reaggregation cultures to assess T cell selection and activation.
- Employed HLA tetramer technology to identify and characterize specific T cell populations.
- Analyzed cytokine profiles of T cell clones upon activation with different MHC ligands.
Main Results:
- CD4(+) T cells selected on DRB1*0401 or DRB1*0404 were activated by the other MHC molecule, demonstrating cross-recognition.
- Identified T cells specific for hemagglutinin (HA) 307-319 restricted by DRB1*0401 but activated by HA 307-319 presented by DRB1*0404.
- Observed altered cytokine profiles in T cell clones upon activation with alternative MHC ligands, persisting even with both molecules present.
Conclusions:
- T cells selected on one MHC class II molecule can be activated by altered self-ligands presented on related MHC class II molecules.
- TCR cross-recognition involving disease-associated HLA alleles can lead to aberrant immune responses, particularly in heterozygous individuals.
- These findings highlight the significance of TCR cross-reactivity in the context of autoimmune disease susceptibility.
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