Identification of a Human CD4-CDR3-like Surface Involved in CD4+ T Cell Function

doi:10.1074/jbc.271.37.22635

Identification of a Human CD4-CDR3-like Surface Involved in CD4⁺ T Cell Function*

From the Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107

^§ To whom correspondence should be addressed:
Kimmel Cancer Institute, Jefferson Medical College, 233 S. 10th St., Philadelphia, PA 19107.
Tel.: 215-503-4552; Fax: 215-923-4153.

↵^‡ Present address: Ares Advanced Technology, 280 Pond St., Randolph, MA 02368.

Abstract

The CD4 molecule is expressed on the surface of helper T cells. This molecule contains four tandem external immunoglobulin-like domains (D1-D4), a transmembrane domain, and a cytoplasmic tail. Through the use of molecular modeling techniques, peptide analogs of the CDR3-like region of the human CD4 molecule, analog hPGP, a cyclized peptide 13 amino acids long, was synthesized and tested for its ability to inhibit proliferation in human mixed lymphocyte reactions. A conservative amino acid substitution was made at position 5 (D → N) to increase its activity and designated hPGP(N). A series of alanine substitution peptides were synthesized based on the sequence of hPGP(N) to determine the importance of each residue to the peptide's function. The substitutions of amino acids in positions 3, 7, and 8 had essentially no effect on the inhibitory activity of hPGP(N), while substitutions of amino acids in positions 4 and 6 increased its inhibitory effect. Alanine substitutions of amino acids in positions 2, 5, and 9 dramatically decreased the inhibitory effect of analog hPGP(N). Molecular modeling of the native CD4-CDR3-like domain suggested that the residues corresponding to positions 2, 5, and 9 of the peptide formed a contiguous surface representing the active site.

Footnotes

↵* These studies were supported by funds provided by the Kimmel Cancer Institute Translational Committee. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

MHC

major histocompatibility complex

MLR

mixed lymphocyte reactions

mAb

monoclonal antibody

TdR

thymidine

TCR

T cell receptor.
- Received April 2, 1996.