Abstract
MHC Ib-restricted CD8+ T cells have been implicated in host defense against Mycobacterium tuberculosis (Mtb) infection. However, the relative contribution of various MHC Ib-restricted T cell populations to anti-mycobacterial immunity remains elusive. In this study, we used mice that lack MHC Ia (Kb-/-Db-/-), MHC Ia/H2-M3 (Kb-/-Db-/-M3-/-), or β2m (β2m-/-) to study the role of M3-restricted and other MHC Ib-restricted T cells in immunity against Mtb. Unlike their dominant role in Listeria infection, we found that M3-restricted CD8+ T cells only represented a small proportion of the CD8+ T cells responding to Mtb infection. Non-M3, MHC Ib-restricted CD8+ T cells expanded preferentially in the lungs of Mtb-infected Kb-/-Db-/-M3-/- mice, exhibited polyfunctional capacities and conferred protection against Mtb. These MHC Ib-restricted CD8+ T cells recognized several Mtb-derived protein antigens at a higher frequency than MHC Ia-restricted CD8+ T cells. The presentation of Mtb antigens to MHC Ib-restricted CD8+ T cells was mostly β2m-dependent but TAP-independent. Interestingly, a large proportion of Mtb-specific MHC Ib-restricted CD8+ T cells in Kb-/-Db-/-M3-/- mice were Qa-2-restricted while no considerable numbers of MR1 or CD1-restricted Mtb-specific CD8+ T cells were detected. Our findings indicate that nonclassical CD8+ T cells other than the known M3, CD1, and MR1-restricted CD8+ T cells contribute to host immune responses against Mtb infection. Targeting these MHC Ib-restricted CD8+ T cells would facilitate the design of better Mtb vaccines with broader coverage across MHC haplotypes due to the limited polymorphism of MHC class Ib molecules.
Highlights
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest communicable diseases, with 1.5 million deaths annually [1]
As T cells are crucial to the control of Mtb infection, it is imperative to decipher the role of different T cell subsets in anti-Mtb immunity for the development of more effective vaccines
We used mutant mice that lack distinct MHC I molecules to characterize immune responses mediated by unconventional T cells during Mtb infection
Summary
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest communicable diseases, with 1.5 million deaths annually [1]. Increasing evidence shows that unconventional T cells restricted by MHC Ib molecules can recognize distinct types of microbial antigens and may contribute to host defense against microbial infection [14, 15]. It remains unclear whether MHC Ib-restricted CD8+ T cells play a protective role during Mtb infection and which MHC Ib molecules may be involved in anti-mycobacterial immunity
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