Mechanisms regulating presentation of pathogen-associated antigens to the immune system directly influences the development of protective immunological memory. Programmed cell death is a vital component of the innate immune response, and most pathogens delay, circumvent, or entirely subvert host cell death by encoding inhibitors of these pathways. While one effect of cell suicide is to rapidly prevent pathogen replication and spread, its ramifications on T cell responses are not well understood. Moreover, recent advances have shown that different cell death programs can induce alternative inflammatory responses, which in turn can directly influence antigen presentation and subsequent adaptive immune responses. Here we will address the fundamental question of how different modes of programmed cell death influence adaptive immunity during virus infection in a natural host. Mouse cytomegalovirus (MCMV) is a natural pathogen of murid rodents, and encodes suppressors of both apoptotic and `necroptotic' cell death. Recombinant viruses lacking one or more of these genes are highly attenuated in the host due to premature death of infected cells, but the impact this has on shaping downstream immunity against MCMV are entirely unknown. We hypothesize that different modes of virus-induced programmed cell death will dramatically influence T cell responses at multiple stages.
Aim 1 of this project will assess how MCMV epitope-specific CD8 and CD4 T cell differentiation, effector function and memory differs following infection with mutant MCMVs that can't inhibit necroptosis and/or apoptosis.
Aim 2 will address whether T cells primed in response to cells dying via these distinct pathways show differential abilities to protect against a heterologous virus infection. This projec will provide new insight into how specific cell death pathways regulate T cell differentiation and memory, and its results will also instruct strategies for rational vaccine design.
The role distinct cell death pathways have in shaping T cell responses during pathogen infection remain largely unclear, and furthering our understanding of this would provide key fundamental insight into how innate and adaptive immunity are linked, and inform us how we might harness these processes to develop better vaccines. This work will distinguish how a virus-infected cell dying via two fundamentally different mechanisms (`apoptosis' or `necroptosis') impacts these processes.
| Seelige, Ruth; Saddawi-Konefka, Robert; Adams, Nicholas M et al. (2018) Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection. Sci Rep 8:13670 |
| Picarda, Gaëlle; Benedict, Chris A (2018) Cytomegalovirus: Shape-Shifting the Immune System. J Immunol 200:3881-3889 |
| Delpoux, Arnaud; Michelini, Rodrigo Hess; Verma, Shilpi et al. (2018) Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells. J Exp Med 215:575-594 |
