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. 2013 Jul 1:4:172.
doi: 10.3389/fimmu.2013.00172. eCollection 2013.

Re-Directing CD4(+) T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Christopher J Holland  1 , David K Cole, Andrew Godkin
Affiliations

Re-Directing CD4(+) T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Christopher J Holland et al. Front Immunol. .

Abstract

Recombinant αβ T cell receptors, expressed on T cell membranes, recognize short peptides presented at the cell surface in complex with MHC molecules. There are two main subsets of αβ T cells: CD8(+) T cells that recognize mainly cytosol-derived peptides in the context of MHC class I (pMHC-I), and CD4(+) T cells that recognize peptides usually derived from exogenous proteins presented by MHC class II (pMHC-II). Unlike the more uniform peptide lengths (usually 8-13mers) bound in the MHC-I closed groove, MHC-II presented peptides are of a highly variable length. The bound peptides consist of a core bound 9mer (reflecting the binding motif for the particular MHC-II type) but with variable peptide flanking residues (PFRs) that can extend from both the N- and C-terminus of the MHC-II binding groove. Although pMHC-I and pMHC-II play a virtually identical role during T cell responses (T cell antigen presentation) and are very similar in overall conformation, there exist a number of subtle but important differences that may govern the functional dichotomy observed between CD8(+) and CD4(+) T cells. Here, we provide an overview of the impact of structural differences between pMHC-I and pMHC-II and the molecular interactions with the T cell receptor including the functional importance of MHC-II PFRs. We consider how factors such as anatomical location, inflammatory milieu, and particular types of antigen presenting cell might, in theory, contribute to the quantitative (i.e., pMHC ligand frequency) as well as qualitative (i.e., variable PFR) nature of peptide epitopes, and hence offer a means of control and influence of a CD4(+) T cell response. Lastly, we review our recent findings showing how modifications to MHC-II PFRs can modify CD4(+) T cell antigen recognition. These findings may have novel applications for the development of CD4(+) T cell peptide vaccines and diagnostics.

Keywords: MHC processing; T cell receptor; T cell repertoire; crystal structure; modified peptide; peptide flanking residue; peptide-major histocompatibility complex class II; vaccine.

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Figures

Figure 1
Figure 1
A structural comparison of pMHC-I and pMHC-II. Although the subunit compositions of MHC-I (PDB: 1ZHL) (A) and MHC-II (PDB: 1KG0) (B) are different, the structural conformation they assume is very similar, illustrating their shared role in presenting antigenic peptides (green) to T cells. (A) MHC-I is comprised of three α-chain domains (1, 2, and 3 in red) and β2m (cyan), whereas (B) MHC-II is comprised of a two domain α-chain (red) and a two domain β-chain (cyan). A top down view of the MHC-I (C) and MHC-II (D) demonstrates the two molecules form similar peptide binding grooves comprised of two anti-parallel α-helices that form a channel in which the peptide can bind in an extended conformation, and eight anti-parallel β-sheets that provide specific peptide binding pockets in the base of the groove. These pockets are lined with polymorphic residues that define the size and chemical characteristics of each pocket, and therefore the specific peptide binding motif and register that can be accommodated by different MHC alleles. TCR binding to pMHC-I (E) and pMHC-II (F) is also conserved. The three complementarity determining loops (CDRs) of the TCR (blue circles) bind in a very similar overall orientation with the TCR α-chain over the N-terminus of the peptide and the TCR β-chain over the C-terminus
Figure 2
Figure 2
Comparison of peptide conformations presented by MHC-I and MHC-II. Cartoon cross sections of the pMHC-I (A) and pMHC-II (B) binding grooves, show the key anchor sites in the floor of each groove determine which peptide can associate and the conformation it can assume. (C) The structural database of pMHC-I complexes shows that peptides presented by a MHC-I molecules (represented as ribbon cartoons) generally assume a central bulged conformation. As peptide length increases, the “closed” nature of the pMHC-I binding groove forces the central residues of the peptide up out of the groove to accommodate the extra residues. (D) In contrast, the pMHC-II binding groove is “open” enabling longer peptide to extend out of the groove at form peptide flanking regions. Thus, peptides presented by MHC-II molecules (represented as ribbon cartoons) generally assume a much flatter conformation in the MHC-II binding groove, irrespective of the length of the peptide presented.
Figure 3
Figure 3
TCRs bind with stronger affinity to pMHC-I compared to pMHC-II. Biophysical studies have shown that TCR/pMHC-I binding affinities are, on average, five times stronger compared to equivalent TCR/pMHC-II interactions (i.e., viral pMHC-I restricted TCRs versus viral pMHC-II restricted TCRs) because of faster on-rate for TCR/pMHC-I binding compared to that of TCR/pMHC-II. These differences could be due to the structural differences in peptide presentation between MHC-I and MHC-II. (A) Cartoon of TCR binding to pMHC-I. The presence of a solvent exposed central bulge for MHC-I peptide presentation may represent a structurally advantageous feature for TCR binding, providing an anchor point that can guide the TCR into the correct binding orientation to engage its cognate ligand. (B) Cartoon of TCR binding to the flatter surface of pMHC-II. This relatively featureless surface provides no dominant structural feature for the TCR to “latch” onto, and may reduce the chance of a productive TCR/pMHC-II interaction occurring (explaining the slower on-rate and weaker affinity compared to TCR/pMHC-I interactions).
Figure 4
Figure 4
Peptide flanking regions are determined during the MHC-II antigen processing pathway. (A) Extracellular protein antigens are endocytosed by tissue resident APCs. (B) The pH of the endosome containing potential antigens progressively decreases, activating proteases which cleave captured proteins. (C) Newly synthesized MHC-II molecules reside in the endoplasmic reticulum (ER) in complex with the MHC-II associated invariant chain (Ii), which “plugs” the MHC-II binding groove, preventing ER derived peptides from premature peptide association. (D) Exocytic vesicles containing precursor Ii:MHC-II complexes then combine with endosomes containing exogenous peptide fragments forming the MHC-II compartment. Formation of the MHC-II compartment results in proteolytic cleavage of the Ii chain leaving a 24 amino acid remnant called the class II-associated invariant-chain peptide (CLIP) within the binding groove of the MHC-II molecule. The acidic pH of the MHC-II compartment and presence of the chaperon, HLA-DM, allows peptide exchange between CLIP and high affinity complementary peptides proteolysed in the endosomal compartment. (E) Peptide selection, that presumably plays a strong role in determining the characteristics of PFRs, is also facilitated by HLA-DM in a process termed “peptide-editing” which ensures that only stable MHC-II peptide complexes are expressed and transported to the cell surface for potential TCR interactions. (F) The final pMHC-II, loaded with exogenous peptide, can also be modified further in a process termed peptide trimming that may play a role in governing PFR length. pMHC-II molecules are then transported to the cell surface for interrogation by CD4+ T cells.
Figure 5
Figure 5
Substitution of Arginine substitutions in the C-terminal flanking region of the native Flu1 peptide increases binding affinity. (A,B) Substitution of arginine at position 11 (blue) in the HA305–320 epitope generates around a twofold increase in TCR binding affinity. (C,D) Cartoon representation of the interaction between the TCR and C-terminal PFR (modeled from PDB: 1FYT). (C) The TCR β-chain is beyond the limits for atomic contacts with HA305–320 P11 (dotted line). (D) Modeling shows that a new interaction, possibly a salt bridge, could be formed between the TCR β-chain and arginine (blue) substituted at position 11 of the HA305–320 peptide. This new interaction could explain the increase in affinity observed for cognate TCR binding to the HA305–320 peptide and HA11R.
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