Functional characterization of H2-M3-restricted CD8⁺ T cells in innate and adaptive immunity

• Main Author: Chow, Michael T.
• Language: English
• Published: University of British Columbia 2010
• Online Access: http://hdl.handle.net/2429/20596

The outcome of many host immune responses to perturbations caused by pathogenic infections is dependent on the coordinated actions between innate and adaptive immune cells. Despite the seemingly clear distinction immune cells belongs either to the innate or adaptive immune system, CD8⁺ T cells that exhibit properties attributed to both compartments of the immune system exist. Specifically, a subset of MHC class Ib molecules, H2-M3, preferentially binds to and presents formylated-peptides to CD8⁺ T cells resulting in their rapid expansion, quick production of cytokines, and provision of cytolytic protection against bacterial infections. The work in this thesis is focused on the discovery and characterization of the immunoregulatory potential of H2-M3-restricted T cells. Specifically, the activation of H2-M3-restricted T cells provided early signals for the efficient priming of antigen-specific CD4⁺ T cell responses following immunization, which translated to augmented CD4⁺ T cell numbers during the acute, effector, and memory phase following bacterial infection. Augmented CD4⁺ T cell responses generated with additional signals derived from activated H2-M3-restricted T cells also significantly increased primary antigen-specific responses by conventional MHC class Ia-restricted CD8⁺ T cells. Importantly, a second MHC class Ib molecule, Qa-1, whose human equivalent is HLA-E, was also identified to augment CD4⁺ T cell responses, in vivo. The ability for H2-M3-restricted T cells to provide help to the helper CD4⁺ T cells, leading to an increase in total numbers, was not the result of an increase in cellular division events, but rather due to an increase in CD4⁺ T cell survival. Using in vitro co-culture assays, it was determined that H2-M3-restricted T cells perform these functions by inducing the maturation of dendritic cells. Interestingly, H2-M3-restricted T cells were found to be more efficient at performing this function, relative to activated natural killer cells. Therefore, the adjuvant-like properties of innate-like H2-M3-restricted T cells, and possibly other MHC class Ib-restricted T cells, are targets with unique attributes that can be harnessed for future vaccine design strategies to potently focus immune responses against microbial infections.