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

摘要: 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 Mtb, but it not fully understood how host-pathogen interactions shape individual antigen-specific populations and their capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, upregulated in response to IFN-{gamma} or nutrient/oxygen deprivation vitro infected macrophages. Using murine aerosol infection model, compared vivo expression kinetics MPT70 constitutively expressed ESAT-6, analysed corresponding phenotype vaccine-protection. For wild-type found that was delayed ESAT-6. This associated with induction less differentiated MPT70-specific cells but, also reduced protection after vaccination. In contrast, an MPT70-overexpressing strain promoted highly KLRG1+CX3CR1+ limited lung-homing Importantly, this could be prevented by vaccination and, overexpressing strain, conferred similar as Together our data indicate high antigen drives towards terminal targeted adjuvanted protein can counteract phenomenon maintaining less-differentiated state. These observations shed new light on provide guidance future designed tip immune-balance favor host. ImportanceTuberculosis, caused constitutes global health crisis massive proportions impact current COVID-19 pandemic expected cause rise tuberculosis-related deaths. Improved therefore ever, lack knowledge hampers development. The present study shows antigens availability drive diminished capacity, survival strategy evade antigens. We demonstrate immunisation such state low differentiation. Future vaccine strategies should explore combinations multiple suggest used readily measurable parameter identify these both preclinical clinical studies.