Article Update

Wednesday, October 21, 2020



Before we delve into the nuts and bolts of TCRdriven signaling events, it is important to recall that Tcells can only recognize antigen when presented within the peptidebinding groove of major histocompatibility complex (MHC) molecules. Furthermore, while the TCR is the primary means by which Tcells interact with the MHCpeptide complex, Tcells also express coreceptors for MHC (either CD4 or CD8) that define functional Tcell subsets. Recall that CD4 molecules act as coreceptors for MHC class II and are found on Thelper cell populations that provide “help” for activation and maturation of Bcells and cytotoxic Tcells (Figure 7.1). CD8 molecules act as coreceptors for MHC class I molecules and are a feature of cytotoxic Tcells that can kill virally infected or precancerous cells (Figure 7.1). Note, however, that the affinity of an individual TCR for its specific MHC–antigen peptide complex is relatively low (Figure 7.2). Thus, a sufficiently stable association with an antigenpresenting cell (APC) can only be achieved by the interaction of several complementary pairs of accessory molecules such as LFA1/ICAM1, CD2/LFA3, and so on (Figure 7.3). These adhesion molecules enable Tcells to associate with DCs and other APCs for the purposes of inspecting the peptides being presented within MHC molecules (Figure 7.4). However, these molecular couplings are not necessarily concerned with intercellular adhesion alone; some of these interactions also provide the necessary costimulation that is essential for proper lymphocyte activation.

Helper and cytotoxic T‐cell subsets are restricted by MHC class

Figure 7.1 Helper and cytotoxic Tcell subsets are restricted by MHC class. CD4 on helper Tcells acts as a coreceptor for MHC class II and helps to stabilize the interaction between the TCR and peptide–MHC complex; CD8 on cytotoxic Tcells performs a similar function by associating with MHC class I.

Figure 7.2 The relative affinities of molecular pairs involved in interactions between Tlymphocytes and cells presenting antigen. The ranges of affinities for growth factors and their receptors, and of antibodies, are shown for comparison.

Figure 7.3 Activation of resting Tcells. Interaction of costimulatory molecules leads to activation of resting Tlymphocyte by antigenpresenting cell (APC) on engagement of the Tcell receptor (TCR) with its antigen–MHC complex. Engagement of the TCR signal 1 without accompanying costimulatory signal 2 leads to anergy. Note, a cytotoxic rather than a helper Tcell would, of course, involve coupling of CD8 to MHC class I. Signal 2 is delivered to a resting Tcell primarily through engagement of CD28 on the Tcell by B7.1 or B7.2 on the APC. ICAM1, intercellular adhesion molecule1; LFA1, lymphocyte functionassociated molecule1; VCAM1, vascular cell adhesion molecule1; VLA4, very late antigen4.

Figure 7.4 Interaction between Tcells and dendritic cells. Scanning electron microscopy analysis of DC–Tcell interactions within a 3D collagen matrix.

Unstimulated lymphocytes are typically nonadherent but rapidly adhere to extracellular matrix components or other cells (such as APCs) within seconds of encountering chemokines or antigen. Integrins such as LFA1 and VLA4 appear to be particularly important for lymphocyte adhesion. The ease with which lymphocytes can alter their adhesiveness seems to be related to the ability of integrins to change conformation; from a closed, lowaffinity state to a more open, highaffinity one (Figure 7.5). Thus, upon encounter of a Tcell with an APC displaying an appropriate MHC–peptide complex, signals routed through the TCR complex ensure that the affinity of LFA1 for ICAM1 is rapidly increased and this helps to stabilize the interaction between the Tcell and the APC. This complex has come to be known as the immunological synapse. Activation of the small GTPase Rap1 by TCR stimulation appears to contribute to the rapid change in integrin adhesiveness. How Rap1 achieves this remains somewhat uncertain, but it is likely that modification of the integrin cytoplasmic tail serves to trigger a conformational change within the integrin extracellular domains in a process that has been termed “insideout signaling.

Figure 7.5 Integrin activation. Integrins such as LFA1 can assume different conformations that are associated with different affinities. The bent headpiece conformation has a low affinity for ligand but can be rapidly transformed into the extended highaffinity conformation by activation signals that act on the cytoplasmic tails of the integrin α and β subunits; a process known as “insideout” signaling.

Share with your friends

Give us your opinion

Note: Only a member of this blog may post a comment.

This is just an example, you can fill it later with your own note.