Abstract
CD4 interactions with class II major histocompatibility complex (MHC) molecules are essential for CD4+ T cell development, activation, and effector functions. While its association with p56lck (Lck), a Src kinase, is important for these functions CD4 also has an Lck-independent role in TCR signaling that is incompletely understood. Here, we identify a conserved GGxxG motif in the CD4 transmembrane domain that is related to the previously described GxxxG motifs of other proteins and predicted to form a flat glycine patch in a transmembrane helix. In other proteins, these patches have been reported to mediate dimerization of transmembrane domains. Here we show that introducing bulky side-chains into this patch (GGxxG to GVxxL) impairs the Lck-independent role of CD4 in T cell activation upon TCR engagement of agonist and weak agonist stimulation. However, using Forster’s Resonance Energy Transfer (FRET), we saw no evidence that these mutations decreased CD4 dimerization either in the unliganded state or upon engagement of pMHC concomitantly with the TCR. This suggests that the CD4 transmembrane domain is either mediating interactions with an unidentified partner, or mediating some other function such as membrane domain localization that is important for its role in T cell activation.
Highlights
T cell development, activation, differentiation and effector functions are driven by signals generated by the recognition of peptides bound to major histocompatibility complex molecules on the surface of antigen presenting cells (APCs)
We report that the addition of bulky side chains to this surface (GVxxL), to introduce steric clashing at this putative dimerization interface, has no impact on CD4 expression but impairs its Lck-independent contribution to T cell activation in response to agonist and weak agonist T cell receptor (TCR)-peptides bound to major histocompatibility complex molecules (pMHC) interactions
To verify that CD4T makes an Lck-independent contribution to T cell activation, we generated 58α-β- T cell hybridomas expressing the 5c.c7 TCR, which recognizes a peptide from moth cytochrome c (MCC 88–93) in the context of I-Ek, along with either CD4WT, CD4T, or no CD4
Summary
T cell development, activation, differentiation and effector functions are driven by signals generated by the recognition of peptides bound to major histocompatibility complex molecules (pMHC) on the surface of antigen presenting cells (APCs). The T cell receptor (TCR) is central to this process. It binds the composite surface formed by the peptide and MHC and relays information about the duration of these interactions to the immune receptor tyrosine-based. Lck-Independent Function of CD4 Linked to GGxxG Motif activation motifs (ITAMs) within the intracellular domains of the associated CD3 signaling modules (CD3γε, δε, and zz,) [1, 2]. The class II MHC co-receptor CD4 plays an important role in this process due to its association with Lck, but CD4 makes an Lck-independent contribution to TCR signaling that is incompletely understood [5, 6]
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