Discrepancy Between Magnitude of Structural Changes and Biological Outcomes

Altered Peptide Ligands: Antagonism

AND SUPERAGONISM

So far, no dramatic structural changes that could account for the magnitude of the different signaling outcomes of various altered peptide ligands (APLs) have been observed in the TCR/pMHC structures, when strong agonist, weak agonist, and antagonist peptides are presented by the same MHC to the same TCR [18,21]. Only slight readjustments occur in the TCR/pMHC interface to accommodate different up-pointing peptide side chains. In the A6 system, the number of peptide-TCR contacts does not correlate with the degree of agonism and antagonism [14,21]. Similarly, in the 2C system, the buried surface does not change much when weak and strong agonists are compared, but the complementarity [18] and the number of TCR/pMHC contacts increases despite the relatively minor substitution of an arginine (strong agonist) for a lysine (weak agonist) at P4. Again, no gross confor-mational changes in the TCR or pMHC are observed, but slight rearrangements in the CDR loops accommodate the different peptides [18].

The correlation of complex half life [22] with the degree of agonism or antagonism is also not clear cut. In both 2C and A6, the strong agonists (SIYR and Tax) have a longer half life (9.2 and 7.5 s) than do weak agonists (3.7 s for H-2Kb-dEV8 and 1.5 s for HLA-A2-V7R). However, by using surface plasmon resonance, agonists have been found in the A6 system that have shorter half lives than do antagonists [23]. An antagonist was converted to an agonist by stepwise filling of a cavity in the TCR/pMHC interface and the biological activity paralleled the TCR/pMHC affinity, not the half life of the complex [23]. Half-lives of TCR/pMHC complexes on the cell surface could be extended by interaction with the coreceptors CD4 and CD8 [24]. Lateral interactions among the TCR/pMHC signaling complexes or interactions with other costimulatory or inhibitory receptors, as in the immunological synapse, may thus form above a certain threshold of TCR/pMHC complex half life [25].

TCR Conformational Variation and Changes

Sufficient numbers of TCR structures are now available to assess the extent of conformational variation that arises in their antigen combining sites. As expected, the four TCR outer CDRs 1 and 2 adopt canonical conformations [26],

Figure 3 Relative orientation of the TCR on top of the MHC and comparison of peptide conformations in class I and class II TCR/pMHC complexes. The MHC helices are shown as light and dark gray tubes for class I and class II, respectively. The CDR loops are colored as in Fig. 2. Lines and axes are colored blue for class II TCRs and orange and red for human and mouse class I TCRs, respectively. (a) Variation in the diagonal (twist) orientation of the six independent TCR/pMHC complexes. The projection of a linear least-squares fit through the centers of gravity of the CDR loops is shown for the six different TCRs. (b) and (c) Variation in the tilt and roll of TCR/pMHC complexes. The pseudo two-fold axes that relate the Va and VP domains of the TCRs to each other are shown for 12 TCR/pMHC structures. This gives a good estimate of the inclination (roll, tilt) of the TCR on top of the MHC, which is a function of the TCR, not the pMHC ligand. One extreme case is the allogeneic BM3.3 TCR, which is shown as a transparent Ca trace. Water molecules filling a large cavity between the TCR and pMHC in this complex are shown as black spheres. (Adapted from Rudolph, M. G. and Wilson, I. A., Curr. Opin. Immunol., 14, 52-65, 2002.)

Figure 3 Relative orientation of the TCR on top of the MHC and comparison of peptide conformations in class I and class II TCR/pMHC complexes. The MHC helices are shown as light and dark gray tubes for class I and class II, respectively. The CDR loops are colored as in Fig. 2. Lines and axes are colored blue for class II TCRs and orange and red for human and mouse class I TCRs, respectively. (a) Variation in the diagonal (twist) orientation of the six independent TCR/pMHC complexes. The projection of a linear least-squares fit through the centers of gravity of the CDR loops is shown for the six different TCRs. (b) and (c) Variation in the tilt and roll of TCR/pMHC complexes. The pseudo two-fold axes that relate the Va and VP domains of the TCRs to each other are shown for 12 TCR/pMHC structures. This gives a good estimate of the inclination (roll, tilt) of the TCR on top of the MHC, which is a function of the TCR, not the pMHC ligand. One extreme case is the allogeneic BM3.3 TCR, which is shown as a transparent Ca trace. Water molecules filling a large cavity between the TCR and pMHC in this complex are shown as black spheres. (Adapted from Rudolph, M. G. and Wilson, I. A., Curr. Opin. Immunol., 14, 52-65, 2002.)

as first described for antibodies [27,28]. A small number of discrete canonical conformations may be able to describe most of the known sequences of the a1,2 and pi,2 loops. At present, three to four canonical structures have been defined for each of these loops [26]. What makes the TCR different from antibodies is the enormous variation seen in both of the central CDR3s (Fig. 3). In antibodies, CDR L3 adopts a well-defined set of canonical structures, but the equivalent CDR3a loop is highly variable in the current set of TCR structures, as well as the CDR3P loop [12]. Thus, the prediction [29] that these CDRs would be most variable and adapt to the pMHC primarily (but not exclusively [30]) through contact with the peptide has been borne out.

Two examples are available to assess the extent of con-formational variation in the CDR loops in the presence of APL. For TCR 2C, only small variations are seen in CDR3P but, for TCR A6, these conformational rearrangements are much larger. Evidence for flexibility in the TCR has also been derived from kinetic and thermodynamic studies [31-33]. Whether these data support a model in which flexible CDRs stabilize or rearrange upon pMHC binding remains an unanswered question. What is consistent so far in both the structural and kinetic/thermodynamic experiments is that conformational rearrangements of the CDRs can provide better complementarity of the TCR to both the MHC [34] and the peptide [18,21].

Alloreactivity

Alloreactivity is the phenomenon in which a strong immune response can be generated against foreign pMHC molecules to which one's T cells have not been previously exposed [35,36]. Thus, an important practical corollary in defining the structural rules of T cell recognition is to explain alloreactivity [37]. So far, three complexes have addressed this issue [30,38,39]. The complex of the BM3.3 TCR with the allogeneic MHC H-2Kb is perhaps the most structurally distinct so far, but the corresponding syngeneic complex is currently not known. The BM3.3 TCR tilts substantially towards the P-chain side (Fig. 3), with the a-chain making few direct contacts with the MHC. In fact, the long central CDR3a is flared back such that it makes no contacts with the peptide and only two with the MHC. The majority of the interactions are with the P-chain, consistent with that proposed for the interaction of H-2Ld with TCR 2C, where an extreme bulge in the C-terminal half of the peptide is likely to increase its interaction with the TCR P-chain [9]. Two recent studies [38,39] suggest that subtle changes in allogeneic MHCs can alter the peptide conformation and location such that the same peptide is presented differently to the TCR. Thus, these structural studies conclude that TCR interaction with the bound peptide strongly affects the alloresponse.

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