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, Copenhagen, Denmark.; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, 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, Copenhagen, Denmark., Jungersen G; Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.; Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark., Aagaard C; Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark., Andersen P; Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., 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, Copenhagen, Denmark rjm@ssi.dk.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2021 Apr 20; Vol. 12 (2). Date of Electronic Publication: 2021 Apr 20.
DOI:	10.1128/mBio.00226-21
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 gamma interferon (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 analyzed 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 protection similar to vaccination with ESAT-6. Together, our data indicate that high in vivo antigen expression drives T cells toward 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. IMPORTANCE Tuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current coronavirus disease 2019 (COVID-19) pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunization with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies. (Copyright © 2021 Clemmensen et al.)
Databáze:	MEDLINE
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