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

doi:10.1016/j.celrep.2021.109378

HLA class-I-peptide stability mediates CD8⁺ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV

Cell Rep. 2021 Jul 13;36(2):109378. doi: 10.1016/j.celrep.2021.109378.

Authors

Clarety Kaseke¹, Ryan J Park², Nishant K Singh³, Dylan Koundakjian¹, Arman Bashirova⁴, Wilfredo F Garcia Beltran⁵, Overbeck C Takou Mbah¹, Jiaqi Ma⁶, Fernando Senjobe⁷, Jonathan M Urbach¹, Anusha Nathan¹, Elizabeth J Rossin⁸, Rhoda Tano-Menka¹, Ashok Khatri⁹, Alicja Piechocka-Trocha¹⁰, Michael T Waring¹⁰, Michael E Birnbaum¹¹, Brian M Baker⁶, Mary Carrington¹², Bruce D Walker¹³, Gaurav D Gaiha¹⁴

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Harvard Radiation Oncology Program, Boston, MA 02114, USA.
³ 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.
⁴ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ 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.
⁷ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Program in Virology, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA 02114, USA; The Broad Institute, Cambridge, MA 02142, USA.
⁹ Massachusetts General Hospital Endocrine Unit and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹¹ 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.
¹² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹³ 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.
¹⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: ggaiha@mgh.harvard.edu.

Abstract

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.

Keywords: CD8+ T cells; HIV; HLA; epitopes; immunodominance; vaccine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
CD8-Positive T-Lymphocytes / immunology*
Female
HEK293 Cells
HIV Infections / immunology*
Histocompatibility Antigens Class I / immunology*
Humans
Immunodominant Epitopes / immunology*
Peptides / immunology*
Protein Denaturation
Protein Stability
Surface Properties

Substances

Histocompatibility Antigens Class I
Immunodominant Epitopes
Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding