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Front. Immunol., 01 July 2013 |

Re-directing CD4+ T cell responses with the flanking residues of MHC class II-bound peptides: the core is not enough

Christopher J. Holland1, David K. Cole1* and Andrew Godkin1,2*
  • 1Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
  • 2Department of Integrated Medicine, University Hospital of Wales, Cardiff, UK

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

Citation: Holland CJ, Cole DK and Godkin A (2013) Re-directing CD4+ T cell responses with the flanking residues of MHC class II-bound peptides: the core is not enough. Front. Immunol. 4:172. doi: 10.3389/fimmu.2013.00172

Received: 24 April 2013; Accepted: 14 June 2013;
Published online: 01 July 2013.

Edited by:

Bruno Laugel, Cardiff University, UK

Reviewed by:

Balbino Alarcon, Consejo Superior de Investigaciones Cientificas, Spain
Daniel M Altmann, Imperial College, UK

Copyright: © 2013 Holland, Cole and Godkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: David K. Cole and Andrew Godkin, Cardiff University School of Medicine, The Henry Wellcome Building, Cardiff, CF14 4XN, UK e-mail:,

David K. Cole and Andrew Godkin have contributed equally to this work.