Dual Role of CD4 in Peripheral T Lymphocytes

Abstract

The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. A variety of accessory molecules further modulate T-cell signaling. Of these, the CD4 and CD8 coreceptors make the most critical contributions to T cell sensitivity in vivo. Whereas, CD4 function in T cell development is well-characterized, its role in peripheral T cells remains incompletely understood. It was originally suggested that CD4 stabilizes weak interactions between TCRs and peptides in the MHC and delivers Lck kinases to that complex. The results of numerous experiments support the latter role, indicating that the CD4-Lck complex accelerates TCR-triggered signaling and controls the availability of the kinase for TCR in the absence of the ligand. On the other hand, extremely low affinity of CD4 for MHC rules out its ability to stabilize the receptor-ligand complex. In this review, we summarize the current knowledge on CD4 in T cells, with a special emphasis on the spatio-temporal organization of early signaling events and the relevance for CD4 function. We further highlight the capacity of CD4 to interact with the MHC in the absence of TCR. It drives the adhesion of T cells to the cells that express the MHC. This process is facilitated by the CD4 accumulation in the tips of microvilli on the surface of unstimulated T cells. Based on these observations, we suggest an alternative model of CD4 role in T-cell activation.

Keywords: CD4; Lck; T lymphocytes; TCR coreceptor; cell-cell adhesion; microvilli.

Figure 1

CD4 and CD8 coreceptors. (A) The CD4 glycoprotein is composed of a single chain. Its functional motifs, such as the Lck-binding site (in magenta) and the palmitoylation site (in yellow), are in the sole intracellular domain. The extracellular part of CD4 is composed of four Ig-like domains, and the MHC binding site is in the N-terminal D1 domain. Short linker connects CD4 extracellular domains with the transmembrane domain. (B,C) Two forms of CD8 exist: the αβ heterodimer (B) and the αα homodimer (C). The α subunit of CD8 contains the Lck-binding site, and the β subunit contains the palmitoylation site. A single Ig-like domain and a long stalk region (in light gray) form the extracellular parts of the CD8 subunits. Binding of CD4 (A) and CD8αβ (B) to MHC is illustrated with the antigenic receptor because these coreceptors support receptor function in T cells. The TCR/CD3 complex is composed of at least eight subunits. CD3 subunits γ, δ, and ε contain one immunoreceptor tyrosine-based activation motif (ITAM; in dark blue) and three ITAMs are in each ζ subunit. Cognate peptides are depicted in dark brown, self-antigens in light brown.

Figure 2

Spatio-temporal organization of T-cell activation. (A) The contact site between T cells and antigen-presenting cells (which form conjugates) is called the immunological synapse due to its similarity to neuronal synapses. Live-cell confocal microscopy reveals the supramolecular organization of molecules within the immunological synapse, with the receptors and effector molecules accumulating in the center of the mature synapse (cSMAC) and adhesion molecules forming a peripheral ring (pSMAC; i.e., the bull's eye model). (B) Motile T cells form asymmetric kinapses instead of stable and symmetric synapses. Kinapses are similar to motile fibroblast cells with lamellipodium (dSMAC), lamella (pSMAC), and uropod (cSMAC). (C) Total internal-reflection fluorescence microscopy reveals that T-cell signaling is initiated in small microclusters that are assembled upon antigenic stimulation in actin-rich distal regions of the immunological synapse (A; dSMAC). Small rings of adhesion molecules and actin surround TCR microclusters and could serve to stabilize those microclusters.

Figure 3

Models of CD4 role in T-cell activation. Model 1 (upper left panel). TCR and CD4 independently interact with pMHC, and the coreceptor stabilizes the receptor-ligand complex. Inactive Lck (yellow) becomes partially activated (light pink). Model 1.2 (upper middle). In this pseudo-dimer model, two TCRs interact with two pMHCs. One MHC always contains an agonist peptide (dark brown), but the other can have a non-stimulating (self) peptide (light brown) instead. The role of CD4 is to crosslink the two receptor-ligand pairs and to thus accelerate signaling. Model 2 (upper right). CD4 delivers the Lck kinase to the formed TCR-pMHC super-complex that has the antigenic peptide. Lck is fully activated (dark pink) by binding to ZAP-70 (not shown) and accommodating open conformation. Model 3 (lower panel). CD4 accumulates at the tips of T-cell microvilli. Independent of TCR, the CD4 that is on microvilli interacts with the pMHC that is assembled on similar membranous protrusions of antigen-presenting cells (APC). This multivalent interaction drives putative changes in the tips of the microvilli and activates Lck; it thus provides T cells and their TCRs with high sensitivity to antigenic peptides. The presented models are not mutually exclusive. Color-coding of CD4, TCR/CD3 complex, and MHCII as in Figure 1.

Figure 4

Microvilli in T-cell activation. (A) A schematic illustration of a microvillus with villin, fimbrin and espin internally cross-linking compact actin bundles, which tightly fill the microvilli. The plasma membrane is also closely associated with the actin bundles via the ezrin, redoxin, and moesin (ERM) proteins; the dynamics of microvilli involve specialized myosins. The tips of the sensory (i.e., hairy) cell microvilli accumulate critical receptors. (B) The peripheral T cells are covered by finger-like protrusions that are reminiscent of microvilli on sensory cells. (C) Molecular organization of CD4 with respect to other T-cell signaling molecules (e.g., TCR) on microvilli remains unknown. These molecules may be randomly distributed (upper panel) or assembled into specific domains (lower panel). (B) Is adapted from Kim et al. (104) licensed under Creative Commons (CC BY 4.0).