A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). Due to the low polymorphism of MHC Ib molecules within the human population, these molecules and Mtb antigens are attractive targets for better vaccine development. Among these, HLA-E has recently 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. The regulatory function of HLA-E/Qa-1 utilizes a variety of mechanisms acting on multiple cell types to inhibit or activate immune responses. 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 cytotoxic 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. In addition, 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. Further, the regulatory effects of Qa-1 during immune stimulation were not limited to Mtb infection, as Listeria-infected Qa-1-/- mice also showed increased cytokine production and inhibitory CD94/NKG2A expression, as did in vitro stimulation with anti-CD3. Our findings reveal that Qa-1 participates in the immune response to Mtb infection by presenting Mtb peptide antigens as well as regulating immune responses, resulting in more effective anti-Mtb immunity, and that it may play a similar role in other infection models

Last modified

• 04/30/2018

Creator

• Yao Bian

DOI

• https://doi.org/10.21985/N24H66

Subject

• Driskill Graduate Training Program in Life Sciences

Keyword

• T cells
• Mycobacterium tuberculosis

Date created

• 2017-01-01

Resource type

• Dissertation

Rights statement

• In Copyright