In vivoantigen expression regulates CD4 T cell differentiation and vaccine efficacy againstMycobacterium tuberculosisinfection

Abstract

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.

Live Attenuated Vaccines against Tuberculosis: Targeting the Disruption of Genes Encoding the Secretory Proteins of Mycobacteria

“…Two homologous secreted proteins, namely Mpt70 (Rv2875) and Mpt 83 (Rv2873), were found to be highly immunogenic in humans and mice [200]. The genes encoding these proteins are conserved in both Mtb and BCG.…”

It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

“…This is not a trivial endeavor as the Mtb genome encodes thousands of proteins, so protective antigen selection alone is a hurdle. For example, antigen selection and dose have been shown to directly influence T-cell differentiation and subsequent protection in therapeutic mouse models where too high antigen burden in vivo reduces vaccine efficacy and drives more terminal differentiation and less memory formation of T cells (380)(381)(382). When we examine clinical stage TB vaccine candidates (based on the Tuberculosis Vaccine Initiative Pipeline Tracker 2021) for preclinical or clinical evidence of the cell subsets reviewed above, it is evident that there is a paucity of surveillance for most innate subsets and a lack of uniformity for exploring adaptive responses (Table 1).…”