Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the αβ T-cell receptor

Abstract

The membrane glycoprotein CD4 enhances antigen-mediated activation of T cells restricted by class II molecules of the major histocompatibility complex (MHC). This positive function has been attributed to the protein tyrosine kinase p56lck (ref. 4), which is noncovalently associated with the cytoplasmic portion of CD4, and is activated on CD4 aggregation. Antigen presentation by MHC class II molecules coaggregates CD4 and the T-cell antigen receptor (TCR alpha beta-CD3). Thus, the mutual specificity of CD4 and TCR alpha beta for the MHC-antigen complex results in the juxtaposition of p56lck and TCR alpha beta-CD3. In contrast, anti-CD4 antibodies can abrogate antigen-induced, as well as anti-TCR-induced T-cell activation, indicating that CD4 might also transduce negative signals. The molecular basis for this opposing function remains unclear. Here we show that the CD4-p56lck complex prohibits the induction of activation signals through the TCR-CD3 complex when not specifically included in the signalling process. This negative effect does not require anti-CD4 treatment, indicating that the induction of distinct negative signals is probably not involved. Rather, the results demonstrate that the CD4-p56lck complex provides prerequisite signals for antigen-receptor-induced T-cell growth and thus characterize a molecular mechanism for functional constraints imposed on T-cell activation by the MHC.

Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

“…On the other hand, the role of p56 ~k after stimulation with 46-61WW cannot be fully determined. Although it is clear that PLC'y1 phosphorylation can occur in the absence of the CD4 cytoplasmic tail, these data cannot rule out the involvement of p56 ~k as several studies have shown that it does not have to be associated with CD4 to exert its effect (42,43).…”

“…However, p56 ~k has also been shown to perform important kinase-independent functions during T cell activation (37). Although previous studies have suggested that neither effective T call stimulation nor CD4-TCR association can occur when CD4 cannot associate with p56 ~k (38)(39)(40)(41), recent studies have implied an opposing view with p56 kk playing a critical role in TCR-mediated fignaling and T cell development in vivo in the absence of coupling to CD4 (42)(43)(44).…”

Lipid Raft Distribution of CD4 Depends on its Palmitoylation and Association with Lck, and Evidence for CD4-Induced Lipid Raft Aggregation as an Additional Mechanism to Enhance CD3 Signaling

“…CD4 can enhance the T cell response regardless of whether it binds to the same or to different MHC molecules as the TCR (2). The engagement of CD4 with ligand or anti-CD4 in solution can positively or negatively affect the outcome of TCR/CD3 stimulation, which appears to be dependent on the concentration of anti-CD4 Ab and the conditions used for costimulation of CD4 (57)(58)(59)(60)(61)(62). The inhibition of CD3/TCR signaling was also observed by cross-linking of CD4 incapable of Lck binding (equivalent to our 2C CD4) (62).…”

Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation

“…First, Lck is involved in ligandinduced TCR internalization and thus may regulate the availability of TCR and the magnitude of T cell signaling (7)(8)(9)(10)(11). Second, separate ligation of TCR and CD4 causes Lck activation and inhibits T cell responses by priming CD4 ϩ T cells for death (12,13).…”