TY - JOUR
T1 - MHC Ib molecule Qa-1 presents Mycobacterium tuberculosis peptide antigens to CD8+T cells and contributes to protection against infection
AU - Bian, Yao
AU - Shang, Shaobin
AU - Siddiqui, Sarah
AU - Zhao, Jie
AU - Joosten, Simone A.
AU - Ottenhoff, Tom H.M.
AU - Cantor, Harvey
AU - Wang, Chyung Ru
N1 - Funding Information:
This work was supported by NIH R01AI040310 and R01AI057460 (to CRW); NIH R21AI127133, EC HORIZON2020 TBVAC2020 Grant No. 64338, the Netherlands Organization for Scientific Research NWO-TOP Grant No. 91214038 and STW Grant No. 13259 (to THMO and SAJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Ying He for technical assistance and Dr. James Forman for providing Qa-1-transfected HeLa cells. Whole cell lysate from Mycobacterium tuberculosis H37Rv were obtained through BEI Resources, NIAID, NIH.
Publisher Copyright:
© 2017 Bian et al.
PY - 2017/5
Y1 - 2017/5
N2 - A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). HLA-E has been identified to present numerous Mtb peptides to CD8+T cells, with multiple HLA-E-restricted cytotoxic T lymphocyte (CTL) and regulatory T cell lines isolated from patients with active and latent tuberculosis (TB). In other disease models, HLA-E and its mouse homolog Qa-1 can act as antigen presenting molecules as well as regulators of the immune response. However, it is unclear what precise role(s) HLA-E/Qa-1 play in the immune response to Mtb. In this study, we found that murine Qa-1 can bind and present Mtb peptide antigens to CD8+T effector cells during aerosol Mtb infection. Further, mice lacking Qa-1 (Qa-1-/-) were more susceptible to high-dose Mtb infection compared to wild-type controls, with higher bacterial burdens and increased mortality. The increased susceptibility of Qa-1-/-mice was associated with dysregulated T cells that were more activated and produced higher levels of pro-inflammatory cytokines. T cells from Qa-1-/-mice also had increased expression of inhibitory and apoptosis-associated cell surface markers such as CD94/NKG2A, KLRG1, PD-1, Fas-L, and CTLA-4. As such, they were more prone to cell death and had decreased capacity in promoting the killing of Mtb in infected macrophages. Lastly, comparing the immune responses of Qa-1 mutant knock-in mice deficient in either Qa-1-restricted CD8+Tregs(Qa-1 D227K) or the inhibitory Qa-1-CD94/NKG2A interaction (Qa-1 R72A) with Qa-1-/-and wild-type controls indicated that both of these Qa-1-mediated mechanisms were involved in suppression of the immune response in Mtb infection. Our findings reveal that Qa-1 participates in the immune response to Mtb infection by presenting peptide antigens as well as regulating immune responses, resulting in more effective anti-Mtb immunity.
AB - A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). HLA-E has been identified to present numerous Mtb peptides to CD8+T cells, with multiple HLA-E-restricted cytotoxic T lymphocyte (CTL) and regulatory T cell lines isolated from patients with active and latent tuberculosis (TB). In other disease models, HLA-E and its mouse homolog Qa-1 can act as antigen presenting molecules as well as regulators of the immune response. However, it is unclear what precise role(s) HLA-E/Qa-1 play in the immune response to Mtb. In this study, we found that murine Qa-1 can bind and present Mtb peptide antigens to CD8+T effector cells during aerosol Mtb infection. Further, mice lacking Qa-1 (Qa-1-/-) were more susceptible to high-dose Mtb infection compared to wild-type controls, with higher bacterial burdens and increased mortality. The increased susceptibility of Qa-1-/-mice was associated with dysregulated T cells that were more activated and produced higher levels of pro-inflammatory cytokines. T cells from Qa-1-/-mice also had increased expression of inhibitory and apoptosis-associated cell surface markers such as CD94/NKG2A, KLRG1, PD-1, Fas-L, and CTLA-4. As such, they were more prone to cell death and had decreased capacity in promoting the killing of Mtb in infected macrophages. Lastly, comparing the immune responses of Qa-1 mutant knock-in mice deficient in either Qa-1-restricted CD8+Tregs(Qa-1 D227K) or the inhibitory Qa-1-CD94/NKG2A interaction (Qa-1 R72A) with Qa-1-/-and wild-type controls indicated that both of these Qa-1-mediated mechanisms were involved in suppression of the immune response in Mtb infection. Our findings reveal that Qa-1 participates in the immune response to Mtb infection by presenting peptide antigens as well as regulating immune responses, resulting in more effective anti-Mtb immunity.
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U2 - 10.1371/journal.ppat.1006384
DO - 10.1371/journal.ppat.1006384
M3 - Article
C2 - 28475642
AN - SCOPUS:85020233933
VL - 13
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 5
M1 - e1006384
ER -
