In Vivo Antigen Expression Regulates CD4 T Cell Differentiation and Vaccine Efficacy against Mycobacterium tuberculosis Infection

• Published in: mBio 2021-04, Vol.12 (2)
• Main Authors: Clemmensen, Helena Strand, Dube, Jean-Yves, McIntosh, Fiona, Rosenkrands, Ida, Jungersen, Gregers, Aagaard, Claus, Andersen, Peter, Behr, Marcel A, Mortensen, Rasmus
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Bacterial Proteins - genetics; Bacterial Proteins - immunology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - microbiology; Cell Differentiation - immunology; Disease Models, Animal; Editor's Pick; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Female; Gene Expression; Genes, Bacterial; Humans; Immunodominant Epitopes - genetics; Immunodominant Epitopes - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Research Article; Tuberculosis Vaccines - genetics; Tuberculosis Vaccines - immunology; Tuberculosis Vaccines - pharmacology; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - prevention & control
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.00226-21

New vaccines are urgently needed against (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 -infected macrophages. Using a murine aerosol infection model, we compared the 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 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 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. 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 lo