Nonclassical MHC Ib-restricted CD8+ T Cells Recognize Mycobacterium tuberculosis-Derived Protein Antigens and Contribute to Protection Against Infection

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.

Qa-1-Restricted CD8+ T Cells Can Compensate for the Absence of Conventional T Cells during Viral Infection

“…For example, MR1 presents vitamin B metabolites, which are unique to bacteria and yeast ( Kjer-Nielsen et al, 2012 ), and M3 binds N-formylated peptides of mitochondrial or prokaryotic origin ( Wang et al, 1991 ). We, therefore, focused on three non-classical molecules, namely, CD1d, Qa-1, and Qa-2, which have been shown to present pathogen-derived antigens ( Fischer et al, 2004 ; Bian et al, 2017 ; Swanson et al, 2008 ; Shang et al, 2016 ).…”

Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair

“…Non-polymorphic MHC representatives, referred to as non-classical MHC for those encoded by genes located within the MHC region and MHC-like molecules for those outside the MHC, exist for both class I and class II proteins, the most diverse being those related to the MHC class I molecules (Adams and Luoma, 2013). While these molecules have been shown to contribute to the recognition of pathogenic microbes, a protective role for these responses has only recently been addressed (Seaman et al, 2000; Shang et al, 2016; Van Rhijn et al, 2015). Our present results propose that non-classical MHCI molecules may have been dominantly maintained as a means to engage in a dialogue with the microbiota.…”

A Promising Listeria-Vectored Vaccine Induces Th1-Type Immune Responses and Confers Protection Against Tuberculosis

“…Novel approaches to TB vaccination are developing rapidly, and 17 vaccine candidates are in the clinical trial (Garg et al, 2014 ). However, how to enhance the synergistic action between CD4 + - and CD8 + -T cells remains worth exploring (Principi and Esposito, 2015 ; Shang et al, 2016 ). LM as an intracellular pathogenic antigen carrier, has the advantage of inducing multivalent innate immunity as well as a cell-mediated immune response (Jiang et al, 2007 ).…”