title: Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype.
abstract: Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+)T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35:01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+)T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-γ) responses were associated with effector memory phenotypes, which were also detected in non-B*35:01-expressing T cells. However, only the B*35:01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+)T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity.
  
  
  OBJECTIVE
  Dengue is an increasingly significant public health problem as its mosquito vectors spread over greater areas; no vaccines against the virus have yet been approved. An important step toward vaccine development is defining protective immune responses; toward that end, we here characterize the phenotype of the immunodominant T cell responses. These DENV-reactive T cells express high levels of the receptor programmed death 1 protein (PD-1), while those from disease-susceptible alleles do not. Not only does this represent a possible correlate of immunodominance, but it raises the hypothesis that PD-1 might be a regulator that prevents excessive damage while preserving antiviral function. Further, as this study employs distinct populations (Nicaraguan and Sri Lankan donors), we also confirmed that this pattern holds despite geographic and ethnic differences. This finding indicates that HLA type is the major determinant in shaping T cell responses.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Ruklanthi
authors.initials: R
authors.lastname: de Alwis
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bangs
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.affiliation: Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Managua, Nicaragua.
authors.forename: Cristhiam
authors.initials: C
authors.lastname: Cerpas
authors.affiliation: Genetech Research Institute, Colombo, Sri Lanka.
authors.forename: Anira
authors.initials: A
authors.lastname: Fernando
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Sustainable Sciences Institute, Managua, Nicaragua.
authors.forename: Lionel
authors.initials: L
authors.lastname: Gresh
authors.affiliation: Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Managua, Nicaragua.
authors.forename: Angel
authors.initials: A
authors.lastname: Balmaseda
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Genetech Research Institute, Colombo, Sri Lanka.
authors.forename: Aruna D
authors.initials: AD
authors.lastname: de Silva
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA Daniela@lji.org.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
mesh_terms: D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D003715:Dengue / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015870:Gene Expression; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D059871:HLA-A24 Antigen / Q000235:genetics / Q000276:immunology; D015797:HLA-B35 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009527:Nicaragua; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D059871:HLA-A24 Antigen; D015797:HLA-B35 Antigen; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma