Identification of Mycobacterial Ribosomal Proteins as Targets for CD4⁺T Cells That Enhance Protective Immunity in Tuberculosis

Abstract

remains a threat to global health, and a more efficacious vaccine is needed to prevent disease caused by We previously reported that the mycobacterial ribosome is a major target of CD4 T cells in mice immunized with a genetically modified strain (IKEPLUS) but not in mice immunized with BCG. Two specific ribosomal proteins, RplJ and RpsA, were identified as cross-reactive targets of , but the breadth of the CD4 T cell response to ribosomes was not determined. In the present study, a library of ribosomal proteins and -predicted peptide libraries were used to screen CD4 T cell responses in IKEPLUS-immunized mice. This identified 24 out of 57 ribosomal 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, the ribosomal 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 the RplJ 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 against .

A Review on T Cell Epitopes Identified Using Prediction and Cell-Mediated Immune Models for Mycobacterium tuberculosis and Bordetella pertussis

“…Subsequent studies described the first, to the best of our knowledge, true genome-wide screen for CD4 T cell epitopes ( 5 ). Subsequent studies report that CD4 T cells can recognize and target epitopes derived from mycobacterial ribosomal proteins and provide protective functions ( 6 , 7 ).…”

HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs

“…We observed that the transcripts of ribosomal proteins of both smaller and larger subunits of ribosome were upregulated in the Δ higB 1 mutant strain. Studies have shown that these ribosomal proteins are able to elicit a strong CD4 + immune response that might be associated with the faster clearance of the mutant strain in host tissues ( Johnson et al, 2017 ; Kennedy et al, 2018 ). In addition to this, expression level of higA 1 (Rv1956), an adjacent gene of higB 1 toxin was also reduced in the Δ higB 1 deletion strain.…”

Boosting bactericidal immunity of a recombinantMycobacterium smegmatisstrain via zinc-dependent ribosomal proteins

“…Induction of strong multifunctional Th1 CD4 T cell responses and reduction of lung pathology and bacterial burdens was noted in RplJ-boosted mice after Mtb challenge (11).…”

“…In a complementary approach, we generated major histocompatibility complex (MHC) class II-restricted T cell hybridomas from IKEPLUS-vaccinated mice and demonstrated that the CD4LJT cell response recognized several components of the mycobacterial ribosome and was localized in the lungs after Mtb challenge. We then extended our investigations by broadly screening all structural proteins of the Mtb ribosome for their ability to be targeted by CD4 T cells in IKEPLUS immunized mice and showed that the mycobacterial ribosome was highly immunogenic (11). Induction of strong multifunctional Th1 CD4 T cell responses and reduction of lung pathology and bacterial burdens was noted in RplJ-boosted mice after Mtb challenge (11).…”

“…We then extended our investigations by broadly screening all structural proteins of the Mtb ribosome for their ability to be targeted by CD4 T cells in IKEPLUS immunized mice and showed that the mycobacterial ribosome was highly immunogenic (11). Induction of strong multifunctional Th1 CD4 T cell responses and reduction of lung pathology and bacterial burdens was noted in RplJ-boosted mice after Mtb challenge (11).…”