Inhibition of CD4+ T cell activation and adhesion by peptides derived from the gp160.
It has been previously demonstrated that the HIV envelope glycoprotein gp160 can inhibit the activation of T cells triggered by phytohemagglutinin, anti-CD3 antibody and Ag, caused in part by the modulation of the expression of CD4. In this study, we show that gp160 is also able to inhibit the Ag-independent adhesion of CD4+ T cells to B cells as anti-CD4 antibodies do. In addition, synthetic peptides (14 to 21 mer) derived from the gp160 sequence and analogous to the putative binding site of gp160 to CD4 (residues 418-460), and also covering residues 460 to 474 inhibit the capacity of both CD4+ T cell proliferation induced by tuberculin and anti-CD3 antibody and adhesion. This was not associated with inhibition of Ca2+ flux in T cell activation. These inhibitory activities are specific because a) CD4+ T cells but not CD8+ T cells are susceptible to their effects, and b) soluble CD4 neutralizes the inhibitory activities. Peptides are, however, about 100- to 1000-fold less potent inhibitors than the native gp160. In addition, they do not induce CD4 modulation. It is thought therefore that at least part of the gp160 inhibitory activity is not secondary to CD4 modulation but may rely either upon steric hindrance of CD4-MHC class II interaction, of CD4/CD3 TCR complex interaction, or upon negative signaling through binding to CD4. The latter hypothesis is suggested by the inhibition by gp160, gp160-derived peptides, and anti-CD4 antibodies of the Ag-independent adhesion of CD4+ T cells. This adhesion process has been previously shown to be mediated by the LFA-1 and CD2 molecules and not by the TCR/CD3 complex and by CD4. Together, these results support the role of part of the 418-460 region of gp160 as a binding site to CD4, and suggest that binding of part of this region to CD4 can alter T cell proliferation and adhesion. It is proposed that these effects are mainly mediated by negative signaling through CD4.
Corado
J
J
Unité 132 INSERM, Hôpital Necker-Enfants Malades, Paris, France.
Mazerolles
F
F
Le Deist
F
F
Barbat
C
C
Kaczorek
M
M
Fischer
A
A
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018801:CD2 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion; D015686:Gene Products, env / Q000737:chemistry / Q000276:immunology*; D019302:HIV Envelope Protein gp160; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D011498:Protein Precursors / Q000737:chemistry / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014373:Tuberculin / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D014373:Tuberculin; D002118:Calcium