PMID- 36442096
OWN - NLM
STAT- MEDLINE
DCOM- 20221206
LR  - 20230530
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 49
DP  - 2022 Dec 6
TI  - Human T cells recognize HLA-DP-bound peptides in two orientations.
PG  - e2214331119
LID - 10.1073/pnas.2214331119 [doi]
LID - e2214331119
AB  - Human leukocyte antigen (HLA) molecules present small peptide antigens to T 
      cells, thereby allowing them to recognize pathogen-infected and cancer cells. A 
      central dogma over the last 50+ y is that peptide binding to HLA molecules is 
      mediated by the docking of side chains of particular amino acids in the peptide 
      into pockets in the HLA molecules in a conserved N- to C-terminal orientation. 
      Whether peptides can be presented in a reversed C- to N-terminal orientation 
      remains unclear. Here, we performed large-scale identification of peptides bound 
      to HLA-DP molecules and observed that in addition to peptide binding in an N- to 
      C-terminal orientation, in 9 out of 14 HLA-DP allotypes, reverse motifs are 
      found, compatible with C- to N-terminal peptide binding. Moreover, we isolated 
      high-avidity human cytomegalovirus (CMV)-specific HLA-DP-restricted CD4(+) T 
      cells from the memory repertoire of healthy donors and demonstrate that such T 
      cells recognized CMV-derived peptides bound to HLA-DPB1*01:01 or *05:01 in a 
      reverse C- to N-terminal manner. Finally, we obtained a high-resolution 
      HLA-DPB1*01:01-CMVpp65((142-158)) peptide crystal structure, which is the 
      molecular basis for C- to N-terminal peptide binding to HLA-DP. Our results point 
      to unique features of HLA-DP molecules that substantially broaden the HLA class 
      II bound peptide repertoire to combat pathogens and eliminate cancer cells.
FAU - Klobuch, Sebastian
AU  - Klobuch S
AUID- ORCID: 0000-0003-1364-0763
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Lim, Jia Jia
AU  - Lim JJ
AUID- ORCID: 0000-0002-6097-6238
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, 
      Australia.
FAU - van Balen, Peter
AU  - van Balen P
AUID- ORCID: 0000-0002-9670-4664
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Kester, Michel G D
AU  - Kester MGD
AUID- ORCID: 0000-0002-8960-7348
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - de Klerk, Wendy
AU  - de Klerk W
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - de Ru, Arnoud H
AU  - de Ru AH
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA 
      Leiden, The Netherlands.
FAU - Pothast, Cilia R
AU  - Pothast CR
AUID- ORCID: 0000-0002-9761-3123
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Jedema, Inge
AU  - Jedema I
AUID- ORCID: 0000-0001-9042-6459
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Drijfhout, Jan W
AU  - Drijfhout JW
AUID- ORCID: 0000-0003-4808-5296
AD  - Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Rossjohn, Jamie
AU  - Rossjohn J
AUID- ORCID: 0000-0002-2020-7522
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, 
      Australia.
AD  - Institute of Infection and Immunity, Cardiff University, School of Medicine, 
      Cardiff CF14 4XN, United Kingdom.
FAU - Reid, Hugh H
AU  - Reid HH
AUID- ORCID: 0000-0001-6929-5001
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, 
      Australia.
FAU - van Veelen, Peter A
AU  - van Veelen PA
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA 
      Leiden, The Netherlands.
FAU - Falkenburg, J H Frederik
AU  - Falkenburg JHF
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
FAU - Heemskerk, Mirjam H M
AU  - Heemskerk MHM
AD  - Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The 
      Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221129
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Amino Acids)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Peptides)
RN  - 0 (HLA-DP Antigens)
SB  - IM
MH  - Humans
MH  - Amino Acids
MH  - Cytomegalovirus
MH  - *Cytomegalovirus Infections
MH  - Histocompatibility Antigens Class II
MH  - *Peptides
MH  - HLA-DP Antigens/immunology
MH  - T-Lymphocytes/immunology
PMC - PMC9894132
OTO - NOTNLM
OT  - HLA-DP
OT  - T cell
OT  - reverse peptides
COIS- The authors declare no competing interest.
EDAT- 2022/11/29 06:00
MHDA- 2022/12/01 06:00
PMCR- 2023/05/29
CRDT- 2022/11/28 17:23
PHST- 2022/11/28 17:23 [entrez]
PHST- 2022/11/29 06:00 [pubmed]
PHST- 2022/12/01 06:00 [medline]
PHST- 2023/05/29 00:00 [pmc-release]
AID - 202214331 [pii]
AID - 10.1073/pnas.2214331119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2214331119. doi: 
      10.1073/pnas.2214331119. Epub 2022 Nov 29.