Browsing by Author "Dai, Rui"

Immune responses against viral infections are mediated through a complex process by diverse populations of cells, that can be harnessed for tumor immunotherapies and vaccinations. Vaccinia virus (VV) is the most studied member of the poxvirus family and is responsible for the successful elimination of smallpox worldwide. It is unique among well-studied viruses in that it replicates solely in the host cytoplasm and is able to elicit one of the longest lasting immunity in recorded human history. Its success in vaccination has led to the development of adjuvants with VV epitopes and recombinant VV vectors for other infectious diseases and cancer immunotherapy. However, the mechanism behind how VV elicits such a strong immune response from the immune system remains insufficiently understood.

Previous studies have shown that although activation of NK cells is critical for the initial control of VV infection, efficient activation of CD8+ T cell response is required for the eradication of VV infection. It has also been demonstrated that gammadelta T cells play an important part in the immune response against VV infection. However, both processes remain relatively undefined. What promotes CD8+ T cell activation and subsequent generation of CD8+ memory T cells in response to VV infection is still not very well dissected, and the mechanisms that govern gammadelta T cells response to VV are relatively unknown. This thesis examines these questions through three main aims: 1) influence of gammadelta T cells on CD8+ T cell activation, 2) gammadelta T cell direct cytotoxicity against VV infection, and 3) mechanisms that govern CD8+ memory T cell formation. The overall goal of this thesis is to understand the mechanisms behind gammadelta T and CD8+ T cells responses against VV infection.

We found that gammadelta T cells play an important role in promoting CD8+ T cell response to VV infection. We showed that gammadelta T cells serve not only as antigen presenting cells to CD8+ T cell activation, but also as mediators of other signals of CD8+ T cell response in vivo. We further demonstrated that cell-intrinsic MyD88 signaling in gammadelta T cells is required for activation of CD8+ T cells. Contrary to conventional expectations, we found that NKG2D expression in both NK and CD8+ T cells only have partial effect on the elimination of VV post-infection. Instead, we found that NKG2D is an important activator of gammadelta T cell cytotoxicity for VV clearance. Lastly, we demonstrated that Notch1, but not Notch2, deficiency increases the formation of CD8+ memory T cells, through modulating the expression of TCF1/Tcf7. We discovered that cleaved Notch1 intracellular domain binds upstream of Tcf7 and controls the expression of Tcf7 for CD8+ memory T cell formation.

These results demonstrated a critical role for gammadelta T cells in viral clearance and the regulation of adaptive T cell response, with insights into the formation of CD8+ memory T cells. Collectively, this dissertation seeks to better understand how gammadelta T and CD8+ T cells respond to VV infection, with the hopes of shedding additional light on the design of more effective vaccine strategies based on the precise manipulation of immune cell populations for infectious diseases and cancer immunotherapy.