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Molecular requirements for T cell recognition by a major histocompatibility complex class II-restricted T cell receptor: the involvement of the fourth hypervariable loop of the Valpha domain.

Thatte J, Qadri A, Radu C, Ward ES - J. Exp. Med. (1999)

Bottom Line: In contrast, the effect of mutating E69 to alanine is less marked.CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade.The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell-antigen-presenting cell interaction.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunology and Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8576, USA.

ABSTRACT
The role of two central residues (K68, E69) of the fourth hypervariable loop of the Valpha domain (HV4alpha) in antigen recognition by an MHC class II-restricted T cell receptor (TCR) has been analyzed. The TCR recognizes the NH2-terminal peptide of myelin basic protein (Ac1-11, acetylated at NH2 terminus) associated with the class II MHC molecule I-Au. Lysine 68 (K68) and glutamic acid 69 (E69) of HV4alpha have been mutated both individually and simultaneously to alanine (K68A, E69A). The responsiveness of transfectants bearing wild-type and mutated TCRs to Ac1-11-I-Au complexes has been analyzed in the presence and absence of expression of the coreceptor CD4. The data demonstrate that in the absence of CD4 expression, K68 plays a central role in antigen responsiveness. In contrast, the effect of mutating E69 to alanine is less marked. CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade. The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell-antigen-presenting cell interaction.

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α-carbon trace of the structurally solved 1934.4 Vα domain  (grey) associated with the modeled 1934.4 Vβ domain (black) (4). HV4α  residues K68 and E69 are shown with their side chains in black. The figure was generated using the programs Bobscript and Raster3D (70, 71).
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Figure 1: α-carbon trace of the structurally solved 1934.4 Vα domain (grey) associated with the modeled 1934.4 Vβ domain (black) (4). HV4α residues K68 and E69 are shown with their side chains in black. The figure was generated using the programs Bobscript and Raster3D (70, 71).

Mentions: To analyze the effects of mutating HV4α residues 68 and 69 of the 1934.4 TCR on antigen responsiveness, WT and mutated α chain genes were transfected with the WT β (Vβ8.2-Jβ2.3) chain into a TCRα−β− thymoma, 58α−β− (40). This murine T cell thymoma line lacks an endogenous TCR, but has a functional CD3–TCRζ complex that can be expressed on the cell surface with the transfected TCR α and β chains. Fig. 1 shows the location of the residues that were targeted for mutagenesis on the X-ray crystallographic structure of the 1934.4 Vα domain (4).


Molecular requirements for T cell recognition by a major histocompatibility complex class II-restricted T cell receptor: the involvement of the fourth hypervariable loop of the Valpha domain.

Thatte J, Qadri A, Radu C, Ward ES - J. Exp. Med. (1999)

α-carbon trace of the structurally solved 1934.4 Vα domain  (grey) associated with the modeled 1934.4 Vβ domain (black) (4). HV4α  residues K68 and E69 are shown with their side chains in black. The figure was generated using the programs Bobscript and Raster3D (70, 71).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192911&req=5

Figure 1: α-carbon trace of the structurally solved 1934.4 Vα domain (grey) associated with the modeled 1934.4 Vβ domain (black) (4). HV4α residues K68 and E69 are shown with their side chains in black. The figure was generated using the programs Bobscript and Raster3D (70, 71).
Mentions: To analyze the effects of mutating HV4α residues 68 and 69 of the 1934.4 TCR on antigen responsiveness, WT and mutated α chain genes were transfected with the WT β (Vβ8.2-Jβ2.3) chain into a TCRα−β− thymoma, 58α−β− (40). This murine T cell thymoma line lacks an endogenous TCR, but has a functional CD3–TCRζ complex that can be expressed on the cell surface with the transfected TCR α and β chains. Fig. 1 shows the location of the residues that were targeted for mutagenesis on the X-ray crystallographic structure of the 1934.4 Vα domain (4).

Bottom Line: In contrast, the effect of mutating E69 to alanine is less marked.CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade.The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell-antigen-presenting cell interaction.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunology and Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8576, USA.

ABSTRACT
The role of two central residues (K68, E69) of the fourth hypervariable loop of the Valpha domain (HV4alpha) in antigen recognition by an MHC class II-restricted T cell receptor (TCR) has been analyzed. The TCR recognizes the NH2-terminal peptide of myelin basic protein (Ac1-11, acetylated at NH2 terminus) associated with the class II MHC molecule I-Au. Lysine 68 (K68) and glutamic acid 69 (E69) of HV4alpha have been mutated both individually and simultaneously to alanine (K68A, E69A). The responsiveness of transfectants bearing wild-type and mutated TCRs to Ac1-11-I-Au complexes has been analyzed in the presence and absence of expression of the coreceptor CD4. The data demonstrate that in the absence of CD4 expression, K68 plays a central role in antigen responsiveness. In contrast, the effect of mutating E69 to alanine is less marked. CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade. The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell-antigen-presenting cell interaction.

Show MeSH
Related in: MedlinePlus