Preferential binding of unusually long peptides to MHC class I and its influence on the selection of target peptides for T cell recognition.

A classic feature of antigen presentation for CD8+ T cell recognition is that MHC class I molecules generally present peptides of 8-10 amino acids in length. However, recent studies have demonstrated that peptides of >10 residues play a significant role in immune surveillance by T cells restricted by some HLA class I alleles. In the present study, we describe several examples of unusually long viral peptides of 11 or 12 residues, recognized by CTLs in the context of HLA-B35. Interestingly, all these immunogenic peptides completely encompass shorter canonical length sequences that conform to the HLA-B35 binding motif, but which fail to stimulate detectable T cell responses. The mechanism for this phenomenon appears to involve the preferential binding to HLA-B35 of the atypically long CD8+ T cell target peptides over the overlapping canonical length sequences. These data suggest that the peptide length specificity of some HLA class I alleles is broad, allowing peptides of >10 residues to sometimes dominate over canonical length class I ligands as targets for T cell recognition.

[1]  Wendy J M van Zuylen,et al.  Potent T cell response to a class I‐binding 13‐mer viral epitope and the influence of HLA micropolymorphism in controlling epitope length , 2004, European journal of immunology.

[2]  Sarah Rowland-Jones,et al.  Structures of Three HIV-1 HLA-B*5703-Peptide Complexes and Identification of Related HLAs Potentially Associated with Long-Term Nonprogression12 , 2005, The Journal of Immunology.

[3]  K. Parker,et al.  Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. , 1994, Journal of immunology.

[4]  James McCluskey,et al.  Have we cut ourselves too short in mapping CTL epitopes? , 2006, Trends in immunology.

[5]  G W Butcher,et al.  Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. , 2001, Immunity.

[6]  M. Davenport,et al.  Contemporaneous fluctuations in T cell responses to persistent herpes virus infections , 2005, European journal of immunology.

[7]  N. Shastri,et al.  ER aminopeptidases generate a unique pool of peptides for MHC class I molecules , 2001, Nature Immunology.

[8]  Natalie A Borg,et al.  CTL Recognition of a Bulged Viral Peptide Involves Biased TCR Selection1 , 2005, The Journal of Immunology.

[9]  Natalie A Borg,et al.  High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I , 2005, Journal of Biological Chemistry.

[10]  H. Rammensee,et al.  Peptide motifs of HLA-B35 and-B37 molecules , 2004, Immunogenetics.

[11]  Muthuraman Sathiamurthy,et al.  Toward a Definition of Self: Proteomic Evaluation of the Class I Peptide Repertoire1 , 2004, The Journal of Immunology.

[12]  J. McCluskey,et al.  The impact of HLA‐B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV , 2007, European journal of immunology.

[13]  D I Stuart,et al.  Bound water structure and polymorphic amino acids act together to allow the binding of different peptides to MHC class I HLA-B53. , 1996, Immunity.

[14]  Nicholas A Williamson,et al.  A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule , 2007, Nature Immunology.

[15]  Z. Weng,et al.  Cytotoxic T cell recognition of allelic variants of HLA B35 bound to an Epstein‐Barr virus epitope: influence of peptide conformation and TCR‐peptide interaction , 1999, European journal of immunology.

[16]  Mark Lindsey,et al.  Complexity among constituents of the HLA-B*1501 peptide motif , 1998, Immunogenetics.

[17]  P. Cresswell,et al.  Impaired assembly and transport of HLA‐A and ‐B antigens in a mutant TxB cell hybrid. , 1986, The EMBO journal.

[18]  Natalie A Borg,et al.  T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide , 2005, Nature Immunology.

[19]  A. Rickinson,et al.  The Importance of Exogenous Antigen in Priming the Human CD8+ T Cell Response: Lessons from the EBV Nuclear Antigen EBNA11 , 2000, The Journal of Immunology.

[20]  L. Frappier,et al.  Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. , 1997, Immunity.

[21]  L. Szekely,et al.  Identification of wild‐type and mutant p53 peptides binding to HLA‐A2 assessed by a peptide loading‐deficient cell line assay and a novel major histocompatibility complex class I peptide binding assay , 1994, European journal of immunology.

[22]  D. Wiley,et al.  Importance of peptide amino and carboxyl termini to the stability of MHC class I molecules. , 1994, Science.

[23]  M. Aidoo,et al.  Molecular analysis of the association of HLA-B53 and resistance to severe malaria , 1992, Nature.

[24]  William S. Lane,et al.  Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle , 1992, Nature.

[25]  J. McCluskey,et al.  The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation , 2005, The Journal of experimental medicine.

[26]  M. Probst-Kepper,et al.  Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*35011 , 2004, The Journal of Immunology.

[27]  H. Rammensee,et al.  Peptides naturally presented by MHC class I molecules. , 1993, Annual review of immunology.

[28]  V. Gnau,et al.  Motif of HLA-B*3503 peptide ligands , 2004, Immunogenetics.