In vivo antigen expression regulates CD4 T cell differentiation and vaccine efficacy against Mycobacterium tuberculosis infection.

Autor:	Clemmensen HS; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.; Department of Health Technology, Technical University of Denmark., Dube JY; Department of Microbiology and Immunology, McGill University, Montréal, Canada.; Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Canada.; McGill International TB Centre, Montréal, Canada., McIntosh F; Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Canada.; McGill International TB Centre, Montréal, Canada., Rosenkrands I; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark., Jungersen G; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.; Department of Health Technology, Technical University of Denmark., Aagaard C; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark., Andersen P; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.; Department of Immunology and Microbiology, University of Copenhagen., Behr MA; Department of Microbiology and Immunology, McGill University, Montréal, Canada.; Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Canada.; McGill International TB Centre, Montréal, Canada.; Department of Medicine, McGill University Health Centre, Montréal, Canada., Mortensen R; Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2021 Feb 03. Date of Electronic Publication: 2021 Feb 03.
DOI:	10.1101/2021.02.02.429488
Abstrakt:	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. Competing Interests: Conflict of interest PA, CAA, RM are co-inventors of patents covering a vaccine that includes both MPT70 and ESAT-6. PA and IR are also co-inventors of patents covering the use of CAF01® as an adjuvant.
Databáze:	MEDLINE
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