HLA class-I-peptide stability mediates CD8+ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV
Clarety Kaseke,
Ryan J. Park,
Nishant K. Singh,
Dylan Koundakjian,
Arman Bashirova,
Wilfredo F. Garcia Beltran,
Overbeck C. Takou Mbah,
Jiaqi Ma,
Fernando Senjobe,
Jonathan M. Urbach,
Anusha Nathan,
Elizabeth J. Rossin,
Rhoda Tano-Menka,
Ashok Khatri,
Alicja Piechocka-Trocha,
Michael T. Waring,
Michael E. Birnbaum,
Brian M. Baker,
Mary Carrington,
Bruce D. Walker,
Gaurav D. Gaiha
Affiliations
Clarety Kaseke
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Ryan J. Park
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Harvard Radiation Oncology Program, Boston, MA 02114, USA
Nishant K. Singh
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Dylan Koundakjian
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Arman Bashirova
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Wilfredo F. Garcia Beltran
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Overbeck C. Takou Mbah
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Jiaqi Ma
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46556, USA
Fernando Senjobe
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Program in Virology, Harvard Medical School, Boston, MA 02114, USA
Jonathan M. Urbach
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Anusha Nathan
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Elizabeth J. Rossin
Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA 02114, USA; The Broad Institute, Cambridge, MA 02142, USA
Rhoda Tano-Menka
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
Ashok Khatri
Massachusetts General Hospital Endocrine Unit and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
Alicja Piechocka-Trocha
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Michael T. Waring
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
Michael E. Birnbaum
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Brian M. Baker
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46556, USA
Mary Carrington
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Bruce D. Walker
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; The Broad Institute, Cambridge, MA 02142, USA; Center for the AIDS Programme of Research in South Africa, Durban 4001, South Africa; Institute for Medical Engineering and Science and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Gaurav D. Gaiha
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Corresponding author
Summary: Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.
