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In vivo antigen expression regulates CD4 T cell differentiation and vaccine efficacy against Mycobacterium tuberculosis infection.
Clemmensen, Helena Strand; Dube, Jean-Yves; McIntosh, Fiona; Rosenkrands, Ida; Jungersen, Gregers; Aagaard, Claus; Andersen, Peter; Behr, Marcel A; Mortensen, Rasmus.
Afiliação
  • Clemmensen HS; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.
  • Dube JY; Department of Health Technology, Technical University of Denmark.
  • McIntosh F; Department of Microbiology and Immunology, McGill University, Montréal, Canada.
  • Rosenkrands I; Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Canada.
  • Jungersen G; McGill International TB Centre, Montréal, Canada.
  • Aagaard C; Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Canada.
  • Andersen P; McGill International TB Centre, Montréal, Canada.
  • Behr MA; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.
  • Mortensen R; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.
bioRxiv ; 2021 Feb 03.
Article em En | MEDLINE | ID: mdl-33564764
New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to IFN-γ or nutrient/oxygen deprivation of in vitro infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analysed their corresponding CD4 T cell phenotype and vaccine-protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination and, against the overexpressing strain, vaccination with MPT70 conferred similar protection as ESAT-6. Together our data indicate that high in vivo antigen expression drives T cells towards terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less-differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune-balance in favor of the host.
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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Guideline Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Guideline Idioma: En Ano de publicação: 2021 Tipo de documento: Article