Identification of Mycobacterial Ribosomal Proteins as Targets for CD4+T Cells That Enhance Protective Immunity in Tuberculosis
ABSTRACTMycobacterium tuberculosisremains a threat to global health, and a more efficacious vaccine is needed to prevent disease caused byM. tuberculosis. We previously reported that the mycobacterial ribosome is a major target of CD4+T cells in mice immunized with a genetically modifiedMycobacterium smegmatisstrain (IKEPLUS) but not in mice immunized withMycobacterium bovisBCG. Two specific ribosomal proteins, RplJ and RpsA, were identified as cross-reactive targets ofM. tuberculosis, but the breadth of the CD4+T cell response toM. tuberculosisribosomes was not determined. In the present study, a library ofM. tuberculosisribosomal proteins andin silico-predicted peptide libraries were used to screen CD4+T cell responses in IKEPLUS-immunized mice. This identified 24 out of 57M. tuberculosisribosomal proteins distributed over both large and small ribosome subunits as specific CD4+T cell targets. Although BCG did not induce detectable responses against ribosomal proteins or peptide epitopes, theM. tuberculosisribosomal protein RplJ produced a robust and multifunctional Th1-like CD4+T cell population when administered as a booster vaccine to previously BCG-primed mice. Boosting of BCG-primed immunity with theM. tuberculosisRplJ protein led to significantly reduced lung pathology compared to that in BCG-immunized animals and reductions in the bacterial burdens in the mediastinal lymph node compared to those in naive and standard BCG-vaccinated mice. These results identify the mycobacterial ribosome as a potential source of cryptic or subdominant antigenic targets of protective CD4+T cell responses and suggest that supplementing BCG with ribosomal antigens may enhance protective vaccination againstM. tuberculosis.