Cross‐linking of the T cell receptor complex with the subset‐specific differentiation antigen stimulates interleukin 2 receptor expression in human CD4 and CD8 T cells

Abstract

Nonpolymorphic interactions between the T cell differentiation antigens CD4 or CD8 and major histocompatibility complex (MHC)-encoded molecules have been postulated to participate in antigen recognition of MHC-restricted T cells. This would imply simultaneous binding of CD4/8 and of the T cell receptor complex (Ti/CD3) to MHC molecules on the stimulator or target cell. In this report experimental evidence is provided that simultaneous binding by antibodies of Ti/CD3 and of CD4 or CD8 leads to the expression of interleukin 2 (IL 2) receptors in resting human T cells and to their subsequent proliferation in the presence of recombinant IL 2 (rIL 2). This could be shown by using a novel anti-CD3 monoclonal antibody (BMA 030) which alone only marginally stimulates highly purified human T cells even when applied in cross-linked form. However, human T cell subpopulations could be stimulated to grow in the presence of rIL 2 when BMA 030 was fixed to a solid support in combination with antibodies to either CD4 or CD8. In limiting dilution experiments, the frequencies of CD4 and CD8 T cells activated by the antibody combinations were similar to those activated by phytohemagglutinin in the presence of irradiated adherent cells. No stimulation was achieved if both or one antibody was applied in soluble form. In contrast, soluble antibodies inhibited activation by solid-phase antibodies. Taken together, cross-linking of Ti/CD3 with CD4/8 seems to be essential for T cell activation in cases of ligands that bind but do not activate T cells on their own--a situation that may reflect the interaction of T cell receptors with MHC-encoded molecules in association with antigen.

Large-scale culture system of human CD4+ helper/killer T cells for the application to adoptive tumour immunotherapy

“…Therefore, Dynabeads-separated CD4+ T cells may be activated through both CD3 and CD4 molecules. Our results are supported by the results of Emmrich et al (1987) who reported that double immobilisation of anti-CD3 and anti-CD4 induced higher proliferation of CD4+ T cells compared with single immobilisation of anti-CD3 mAb. Thus, the separation procedure of CD4+ T cells using Dynabeads has two advantages over a method using a cell sorter; (1) The procedure is simple and rapid; (2) Dynabeads preparation causes augmented proliferation of CD4+ T cells against immobilised anti-CD3 plus IL-2.…”

Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA.

“…On the other hand, several recent reports highlight the importance of a physical association between CD4 and CD3-Ti complex during T-cell activation. First, cross-linking of CD3-Ti complex with CD4 molecule leads to synergistic activation, resulting in induction of IL-2 responsiveness and lymphoproliferation (33,34). Second, transfection of the CD4 gene enhances the reactivity of T-cell hybridomas if the stimulator cells express class II MHC molecule (35).…”

A second subunit of CD8 is expressed in human T cells.

“…It is unclear whether this effect is due to a negative regulatory signal transmitted directly to T cells, or whether there is steric hindrance of TCR crosslinking by the presence of anti-CD4 or anti-CD8 antibodies (Owens and Fazekas de St Groth, 1987). In contrast, when anti-CD4 or anti-CD8 monoclonal antibodies are cross-linked to anti-TCR antibodies, a marked synergy in activation is observed (Emmrich et al, 1987;Walker et al, 1987). It has also been speculated that CD4 or CD8 may become physically associated with the TCR (Saizawa et al, 1987;Takada and Engleman, 1987;Rivas et al, 1988).…”