Trends in Immunology
ReviewInsight into the basis of autonomous immunoreceptor activation
Section snippets
The pre-T cell receptor as a developmental checkpoint
Mature αβ T cell receptors (TCRs) are heterodimeric integral membrane proteins present on the surface of T-lymphocytes. αβTCRs can function in the recognition of foreign antigenic peptides that are presented on the surface of virally infected cells by class I major histocompatibility (MHC-I) molecules. TCR engagement in secondary lymphoid tissue results in the initiation of intracellular signaling cascades via the associated CD3 subunits and leads to activation and clonal expansion to produce a
The relationship between oligomerization and autonomous signaling
Despite its similarity to the αβTCR, no bona fide pTCR ligand has been identified. This, coupled with reports suggesting class I and class II MHCs are dispensable for β-selection 8, 9 has led to suggestions that the pTCR functions in a ligand-independent manner. This hypothesis is consistent with reports suggesting that the pTCR is constitutively endocytosed [10] in a fashion similar to that of stimulated αβTCR [11].
The recently determined crystal structure of the pTCR extracellular domain has
The importance of pTCR extracellular domains
Although the pTCR superdimerization model provides an elegant explanation for how successful TCR β gene arrangement is monitored, it is at odds with reports that transgenic mice expressing a mutant pTα chain lacking the extracellular domain can proceed past the β-selection checkpoint 16, 17. Indeed, these reports, together with the lack of sequence conservation in the cytoplasmic domains of the pre-Tα, suggest that only the transmembrane domain of the pre-Tα might be important for function. How
Extracellular pTCR organization
One interesting question raised by the structure of the pTCR superdimer is whether the molecule can act in cis and in trans. Although there is little evidence with regard to this issue, a cis arrangement appears to be the most likely because the pTCR is internalized and localized constitutively in lysozymes in the absence of cell–cell interactions 10, 12. However, this does not preclude the possibility of the pTCR acting in trans in some instances. Intriguingly, a cis arrangement would
pTCR stoichiometry and assembly with CD3
A major driving force for assembly between αβTCR and CD3 is via polar interactions between specific charged residues within the transmembrane domains [23]. Each of the three basic TCR transmembrane residues interacts with a pair of acidic residues present in the three CD3 signaling dimers (Figure 1a). Furthermore, assembly takes place in a defined order, with CD3ɛδ first recruited to the TCRα, followed by CD3ɛγ interacting with TCRβ and finally the association of CD3ζζ with TCRα [23]. Both of
The pTCR cytoplasmic tails and intracellular signaling
The mature TCRα and TCRβ chains have unusually short cytoplasmic regions of only three amino acids that contain no identifiable signaling motif. Instead, signal transduction is initiated exclusively by the ITAMs of the associated CD3 subunits. However, the cytoplasmic region in murine and human pTα is considerably larger (30 and 114 amino acids, respectively). The biological significance of the pTα cytoplasmic region remains controversial with some reports suggesting it is dispensable for T
An analogous mechanism in pre-BCR?
B cell receptors (BCRs) also function in the recognition of antigens but differ from TCRs in that their targets are unprocessed proteins that do not require presentation by MHC molecules. Following antigen engagement, BCRs stimulate B cell proliferation and differentiation to generate a population of antibody-secreting plasma B cells and memory B cells. From a structural perspective, BCRs are essentially membrane-bound antibodies and are composed of two identical heavy chains (HC) and light
Why does the pBCR employ a different mechanism?
The question remains of why have the pTCR and pBCR evolved different mechanisms to perform the task of monitoring successful gene rearrangement? One explanation could lie in subtle differences in the functional requirements, e.g. to bias or not to bias the resulting repertoire. Alternatively, the differences that are apparent in these pre-immunoreceptors might reflect the alternate approaches employed by their mature counterparts. The αβTCR most likely exists on the cell surface as a mixture of
Summary and future perspectives
The past few years have seen considerable advances in our understanding of the mechanism responsible for pTCR and pBCR function. It is now clear that pTCR does not require a soluble ligand for activation. Instead, pTCR autonomous signaling is intrinsically linked to the formation of a ‘superdimer’ on the cell surface. This arrangement allows the invariant pTα chain to act as a molecular sensor to probe the success of TCRβ gene rearrangement in a way that does not bias the mature repertoire.
Acknowledgments
We thank past and present members of the team who contributed to our understanding of pre-TCR assembly. This work was supported by grants from the National Health and Medical Research Council of Australia and the Australian Research Council (ARC). J.R. is supported by an ARC Federation Fellowship.
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Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling
2016, StructureCitation Excerpt :Oligomerization is common among cell-surface receptors in resting as well as signal transduction active states and appears to be critical for receptor function (Metzger, 1992). Oligomerization is observed in such diverse families of receptors as immunoreceptors (Ramsland et al., 2011), T cell receptors (Berry et al., 2011; Choudhuri et al., 2005), B cell receptors (Schamel and Reth, 2000), growth factors (DiGabriele et al., 1998), and hormone receptors (Angers et al., 2002). Oligomerization is triggered by the inter-molecular engagement of extracellular and/or intracellular domains.
Structure of the chicken CD3εδ/γ heterodimer and its assembly with the αβT cell receptor
2014, Journal of Biological ChemistryCitation Excerpt :All jawed vertebrates have an adaptive immune system that includes the genes to make antibodies, MHC and TCR (40). Furthermore, all mature TCR genes cloned to date (excluding pre-Tα (41, 42)) encode proteins with very short cytoplasmic domains that are unlikely to contain signaling motifs and are therefore thought to depend on CD3 or CD3-like signaling modules to transmit information to the intracellular signaling machinery (43). Analysis of CD3 loci across jawed vertebrate species suggests that the three genes present in mammals arose from two separate gene duplication events, the latter of which facilitated the divergence of CD3γ and CD3δ genes to produce two distinct CD3ϵγ and CD3ϵδ signaling modules.
The versatility of the αβ T-cell antigen receptor
2014, Protein Science