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Evolutionarily conserved amino acids that control TCR-MHC interaction.

Philippa Marrack¹, James P Scott-Browne, Shaodong Dai

¹Howard Hughes Medical Institute, University of Colorado Denver Health Science Center, Denver, Colorado 80206, USA. marrackp@njc.org

Annual Review of Immunology

|February 29, 2008

Summary

Mature T cells have T cell receptors (TCRs) with weaker binding to major histocompatibility complex (MHC) due to negative selection. Conserved TCR residues in CDR1/CDR2 bind exposed MHC helices, with rules varying for MHC class I and II recognition.

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Area of Science:

Immunology
Structural Biology
Molecular Recognition

Background:

The precise rules governing T cell receptor (TCR) interactions with major histocompatibility complex (MHC) and peptides remain unclear.
Negative selection in the thymus eliminates T cells with high TCR reactivity to self-MHC, resulting in mature T cells with attenuated responses.
The inherent flexibility of TCR-MHC interaction sites complicates the identification of specific binding interfaces.

Purpose of the Study:

To re-evaluate the contact points between TCRs and MHC in solved complex structures.
To elucidate the conserved structural and sequence features governing TCR-MHC binding.
To investigate potential differences in recognition rules between MHC class I (MHCI) and MHC class II (MHCII).

Main Methods:

Analysis of solved crystal structures of TCR-MHC complexes.
Identification of conserved amino acid residues within TCR complementarity-determining regions (CDRs).
Mapping of TCR-MHC contact sites and assessment of MHC surface accessibility.

Main Results:

Conserved amino acids in TCR CDR1 and CDR2 engage with exposed regions of MHC alpha-helices.
These exposed MHC regions are facilitated by small amino acids, allowing for flexible TCR binding.
TCR binding specificity is linked to variable (V) region families, with distinct recognition patterns observed for MHCI versus MHCII.

Conclusions:

TCR-MHC interactions are governed by conserved residues in CDR1/CDR2 binding to flexible MHC surfaces.
Negative selection shapes the repertoire of TCRs available for MHC recognition in mature T cells.
Distinct molecular recognition mechanisms likely exist for TCR binding to MHCI and MHCII.