Direct involvement of the CDR3-like domain of CD4 in T helper cell activation

TY - JOUR

T1 - Direct involvement of the CDR3-like domain of CD4 in T helper cell activation

AU - McDonnell, J M

AU - Blank, K J

AU - Rao, P E

AU - Jameson, B A

AU - McDonnell, James

PY - 1992/9/1

Y1 - 1992/9/1

N2 - The CD4 glycoprotein, a member of the Ig super-family, has long been known to play an important role in the immunologic activation of Th cells. The precise manner in which CD4 participates in this activation process is not yet understood. In an attempt to further define its role in Th cell activation, we modeled the D1 domain of the murine CD4 protein (L3T4) based on the experimentally determined high resolution structure of the human CD4 protein. Because the D1 domain of CD4 strongly resembles the V kappa chain of an antibody, we addressed the question of whether the CDR-like regions of CD4 are also involved in mediating protein-protein interactions. Consequently, we used the modeled L3T4 structure as a template in the design of conformational mimics of the CDR3-like region (residues 86-94). Only the analog designed to mimic both the sequence and conformation of this region exhibited highly specific inhibition of CD4-dependent responses. Because the inhibitory activity could be localized to the Th cell itself, it appears that this analog acts by uncoupling a CD4 association (independent of an APC) critical to generating a proliferative response.

AB - The CD4 glycoprotein, a member of the Ig super-family, has long been known to play an important role in the immunologic activation of Th cells. The precise manner in which CD4 participates in this activation process is not yet understood. In an attempt to further define its role in Th cell activation, we modeled the D1 domain of the murine CD4 protein (L3T4) based on the experimentally determined high resolution structure of the human CD4 protein. Because the D1 domain of CD4 strongly resembles the V kappa chain of an antibody, we addressed the question of whether the CDR-like regions of CD4 are also involved in mediating protein-protein interactions. Consequently, we used the modeled L3T4 structure as a template in the design of conformational mimics of the CDR3-like region (residues 86-94). Only the analog designed to mimic both the sequence and conformation of this region exhibited highly specific inhibition of CD4-dependent responses. Because the inhibitory activity could be localized to the Th cell itself, it appears that this analog acts by uncoupling a CD4 association (independent of an APC) critical to generating a proliferative response.

KW - Amino Acid Sequence

KW - Animals

KW - Antigens, CD4

KW - Antigens, Differentiation, T-Lymphocyte

KW - Immunoglobulin Variable Region

KW - Interleukin-2

KW - Lymphocyte Activation

KW - Mice

KW - Molecular Sequence Data

KW - Protein Conformation

KW - T-Lymphocytes, Helper-Inducer

M3 - Article

C2 - 1387146

SN - 0022-1767

VL - 149

SP - 1626

EP - 1630

JO - Journal of Immunology

JF - Journal of Immunology

IS - 5

ER -