Date Published: June 7, 2016
Publisher: Public Library of Science
Author(s): Shaobin Shang, Sarah Siddiqui, Yao Bian, Jie Zhao, Chyung-Ru Wang, David M. Lewinsohn.
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.
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 . Due to the emergence of multidrug-resistant Mtb strains, co-infection with HIV, and the failure of BCG vaccine to control adult pulmonary TB [1, 2], there is an urgent need for new and more effective TB vaccines. However, achieving this goal relies on further investigation of the properties of protective T cells during Mtb infection . It is well established that immune protection against Mtb infection is dependent on a robust Th1 response, mediated by CD4+ T cells [4–7], while CD8+ T cells are required for optimal immunity [8–11]. The cytokines IL-12, IFN-γ and TNF-α are critical for the control of Mtb infection . Current subunit vaccine candidates target conventional CD4+ and MHC Ia-restricted CD8+ T cells . However, 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]. Yet, 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.
In this study, we defined the relative contribution of MHC Ia-, M3- and other MHC Ib-restricted CD8+ T cells in Mtb infection by comparing CD8+ T cell responses in B6, Kb-/-Db-/-, Kb-/-Db-/-M3-/- and β2m-/- mice upon aerosol infection with virulent Mtb. Unlike their role in Listeria infection, M3-restricted CD8+ T cells do not play a dominant role in the MHC Ib-restricted CD8+ T cell responses to Mtb infection. This finding highlights the differential roles of various MHC Ib-restricted responses in immunity against distinct microbial pathogens. While CD1-restricted and MR1-restricted T cell responses have been characterized in the context of Mtb infection, our data showed that neither CD1d nor MR1 serve as major restriction elements for the Mtb-specific MHC Ib-restricted CD8+ T cells found in Kb-/-Db-/-M3-/- mice. In fact, we found a substantial fraction of these Mtb-specific unconventional CD8+ T cells were restricted by Qa-2, which is known to present a more diverse array of peptides than other MHC Ib molecules . Qa-2-restricted T cell responses have been implicated in anti-tumor immunity  and antiviral immunity  . However, this is the first study to describe a role for Qa-2 in host defense against bacterial infection. As HLA-G is a possible functional homolog of Qa-2 , it will be of great interest to explore whether HLA-G-restricted Mtb-specific T cell responses can be detected in patients with active TB or BCG-vaccinated individuals.