Regulation of T helper‐B lymphocyte adhesion through CD4‐HLA class II interaction

Abstract

Antigen-independent adhesion of CD4+ T lymphocytes to Epstein-Barr virus (EBV)-transformed B cells is mediated by CD2/lymphocyte function-associated antigen (LFA)-3 and LFA-1/intracellular adhesion molecule (ICAM)-1. Although some anti-CD4 antibodies block the antigen-independent adhesion of CD4+ T lymphocytes, the CD4-HLA class II interaction does not appear to significantly contribute to the forces of cell adhesion since CD4+ T cells equally bind HLA class II+ and HLA class II- mutant B cells. In addition, conjugates formed between CD4+ T cells and HLA class II- B cells remain stable for at least 1 h while CD4+T/HLA class II+ B cell conjugate percentages promptly drop off. Down-regulation of CD4 or spontaneous low expression of CD4 also results in a persistance of conjugates formed with B cells. The role of the CD4-HLA class II interaction has been further studied by investigating the inhibitory effect of synthetic 12-mer peptides analogous to HLA class II and containing the Arg-Phe-Asp-Ser sequence conserved in the beta 1 domain. These peptides were previously found to inhibit HLA class II-restricted T cell responses, this sequence being thought to be involved in CD4-HLA class II interaction. These peptides block conjugate formation of CD4+ resting T cells or clones but not of CD8+ T cells, by interacting with the T cells as shown by preincubation experiments. Down-regulation of CD4 or spontaneous low expression results in the loss of the inhibitory activity. The peptide-mediated inhibition is neutralized by a soluble dimeric CD4 molecule. Alteration within the Arg-Phe-Asp-Ser sequence results in a significant loss of inhibition. It is thus proposed that the CD4-HLA class II interaction negatively regulates antigen-independent adhesion of T cells, this interaction involving the highly conserved Arg-Phe-Asp-Ser sequence in the HLA class II beta 1 sequence as a CD4-binding site.

Regulation of LFA‐1‐mediated T cell adhesion by CD4

“…6). It is noteworthy that neutralization by soluble CD4 of the DR12 peptide inhibitory effect was not equimolar, suggesting that not all peptides had the optimal conformation, as already observed in previous experiments [6], Finally, two gp 160-derived peptides ana logous to positions 418-434 and 449-464, respectively, known to participate to the binding of gpl60 to CD4 [18] were more potent in suppressing the adhesion of resting CD4+ Tcells than that of anti-CD3-or NKlL16-activated T cells ( Fig. 7; p <0.001 and p <0,0001, respectively, for concentrations of 0.4 pM and 4 jam).…”

“…4, the anti-CD4 antibody OKT4a was able to inhibit both anti-CD3 and NKIL16 activated T cell adhesion and adhesion of resting CD4+ T cells [6], In addition, this antibody was equally effective on the adhet tig/ml (Fig. 4 a).…”

“…All these reagents have previously been shown to specifically inhibit adhesion of resting CD4+ T cells ( [6]; Corado et al; submitted). Initially it was checked that Tcell incubation with anti-CD3 or NKIL16 antibodies did not significantly alter CD4 expression compared to resting cells (data not shown).…”

“…LFA-1 (CDlla-CD18) binding to ICAM-1 (CD54) or ICAM-2 ligands and CD2 binding to LFA-3 (LCD58; [1][2][3]), Such adhesion processes are required for T cell activation and effector functions. This has been demonstrated in blocking experiments using specific mAb [4][5][6] and showing altered binding and functions of T ceils defective in LFA-1 expres sion [6][7][8], as well as poor binding and cytotoxic function of T cells towards ICAM-1" LFA-3" Burkitt B cells [9]. Finally, transfection of murine fibroblasts with ICAM-1 or LFA-3, in association with MHC molecules, leads to optimal binding and activation of specific T cells [10][11][12].…”

“…We have previously provided experimental evidence sup porting the hypothesis that the CD4-MHC class II interac tion could down-regulate the low-affinity binding of resting CD4+ T cells to B cells ( [6], Mazerolles et al, Hum. I m m u n o lin press).…”