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Interact Differently with 
2-Microglobulin of the Class I Molecules H-2Kb and Thymic Leukemia Antigen, While Similarly with Their 3 Domains1
* Department of Laboratory Medicine and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
The murine CD8 glycoprotein interacts with both classical MHC class
I molecules and some nonclassical molecules, including the thymic
leukemia Ag (TL). TL binds preferentially to CD8
homodimers with
a 10-fold higher affinity than H-2Kb class I molecules. To
understand the molecular basis for this difference, we created a panel
of CD8 mutants and tested the ability of the CD8 homodimers to
bind to H-2Kb tetramers and TL tetramers. Mutations in
three CD8 residues located on the complementarity-determining
region-like loops contacting the negatively charged loop in the 3
domain of MHC class I greatly reduced binding to both tetramers.
Because TL and H-2Kb class I sequences are highly conserved
in the 3 domain of MHC class I, this suggests that CD8 contacts the
3 domain of TL and H-2Kb in a similar manner. In
contrast, mutations in residues on the A and B 
strands of CD8 that
are involved in contact with 2-microglobulin affected
interaction with the H-2Kb tetramer, but not the TL
tetramer. Therefore, the orientation of interaction of TL with CD8
appears to be different from that of H-2Kb. The unique high
affinity binding of TL with CD8 is most likely a result of amino
acid differences in the 3 domain between TL and
H-2Kb, particularly at positions 198 (K to D) and
228 (M to T), which are contact residues in the
CD8-H-2Kb cocrystal.
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