Superantigen staphylococcal enterotoxin B-induced T-helper cell activation is independent of CD4 molecules and phosphatidylinositol hydrolysis.

Abstract

The role of the CD4 molecule in activation of T-helper cells was examined by investigating the effect of an anti-CD4 monoclonal antibody (Leu3a) in conventional peptide antigen-specific cloned T-helper cells that are also reactive to staphylococcal enterotoxin B (SEB). These T-helper cell clones are CD4+/CD45RO+/T-cell antigen receptor «-chain variable region 12-positive and can respond to nominal peptide antigens and SEB by proliferation in the presence of class II major histocompatibility complex-expressing accessory cells. Although antigen and SEB were comparable in their ability to induce proliferative responses, interleukin 2 (IL-2) production, and IL-2 receptor a-chain expression, stimulatin with SEB failed to trigger phosphatidylinositol hydrolysis or a rise in the intracellular free calcium ion concentration. Leu3a treatment inhibited antigen-induced proliferative responses of T cells with concomitant suppression of IL-2 production and IL-2 receptor expression. In contrast, SEB-induced responses were unaffected by Leu3a. These findings indicate that the functional consequences of binding (ligation) of conventional antigen and of superantigen with the T-cell receptor are distinct in the context of both signal transduction pathways and participation of CD4 molecules.Superantigens are molecules that are recognized differently from conventional antigens by responsive T cells. Superantigens are characterized by their ability to bind to a component or components of class II major histocompatibility complex (MHC) molecules and to stimulate T cells in a ,B3chain variable region (V9)-specific manner (1). Conventional antigens bind within a polymorphic groove on class II MHC molecules and interact only with T cells bearing unique a and ,B T-cell antigen receptors (TCRs). Superantigens interact with class II molecules outside the antigen groove (2) and stimulate distinct Vg-expressing T cells (1 Cells. Antigen-specific human T-cell clones specific for tetanus toxoid and for purified protein derivative (PPD) were developed as described (7). The clones used, PPD3.2, PPD3.5, and Tt4.2, express the phenotype CD3+/CD4+/ CD45RO+ (UCHL1+). These clones also react with mAb to V,12 (T Cell Science, Cambridge, MA). They proliferate and secrete IL-2 after stimulation with antigen in the presence of irradiated autologous Epstein-Barr virus-transformed B cells as antigen-presenting cells (APC), designated EBV300 for clones PPD3.2 and PPD3.5 and EBV400 for Tt4.

Superantigens: The Paradox of T-Cell Activation versus Inactivation

“…Interestingly, mono clonal antibodies against the TCR-like anti-CD3 or anti-a/(3 monoclonal antibody are unable to acutely induce the loss of L-selectin indicating that the TCR-mediated signal cas cade initiated via Sag differs from that triggered by aTCR monoclonal antibody [13]. This conclusion is supported by results showing that, in contrast to nominal antigen, Sag do not induce the hydrolysis of phosphatidylinositol in Sag-re active T-cell clones [14]. Furthermore, compared to peptide antigens, the influx of Ca2 seems to be at variance after cross-linking of the TCR with Sag [15].…”

Bacterial Superantigens Bypass Lck-Dependent T Cell Receptor Signaling by Activating a Gα11-Dependent, PLC-β-Mediated Pathway

“…For example, although most SAg are recognized in the context of MHC class II molecules, they are able to activate not only CD4 + T cells but also CD8 + T cells (Fuller and Braciale, 1998;Herrmann and MacDonald, 1993;Webb and Sprent, 1990), implying that the conventional CD4 and CD8 coreceptor assignment is not operational in these responses. Consistent with this observation, human T cell responses to some staphylococcal SAg such as enterotoxin B (SEB) or C-1 (SEC1) have been reported to be resistant to CD4 blockade and do not require expression of the CD4 coreceptor in the responding T cells (Bavari and Ulrich, 1995;Oyaizu et al, 1992). These observations suggest that human T cell responses to bacterial SAg do not require the CD4-associated Lck.…”

“…SEE-induced immune responses in vivo have been mostly associated with a Th1 profile (Gehring et al, 1998;Hamel et al, 1995), consistent with the dispensability of Lck for immune responses to bacterial SAg. Also, the CD4 independence of T cell responses to some bacterial SAg (Herrmann and MacDonald, 1993;Webb and Sprent, 1990) and the ability to activate CD8 + T cells despite these toxins being recognized in the context of MHC class II binding (Bavari and Ulrich, 1995;Oyaizu et al, 1992) would be a reflection of the ability of these toxins to bypass the requirement for the conventional CD4 or CD8 coreceptor and its associated Lck kinase to initiate TCR signaling.…”

gp160 of HIV or anti‐CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK‐2 activities in human peripheral CD4+ T lymphocytes

“…This PTK is indeed activated in response to CD4 ligands binding and has been shown to regulate CD4-mediated inhibition of T cell adhesion [64]. It has been proposed that gp120 ligation of CD4 activates the CD4-associated tyrosine kinase ~5 6 ' '~ and inactivates TCR function by uncoupling the receptor from early signaling events [57,651. This effect may involve a gpl20-mediated sequestration of ~5 6 ' '~.…”