The Role of Tumour Necrosis Factor Receptor Family Members CD137 (4-1BB) and CD30 in Antiviral T Cell Responses

The tumour necrosis factor receptor (TNFR) superfamily is a collection of immunomodulatory molecules that aid in the fine-tuning and regulation of immunity through stimulatory or inhibitory signalling functions at various stages of the T cell response. In this thesis, I investigate the roles of TNFR family members CD137 (4-1BB) and CD30 in antiviral T cell responses, most notably during influenza virus infection. Using a prime-boost vaccine immunization regimen in which mice are infected with mild influenza and then boosted intranasally with a replication defective adenovirus containing the influenza nucleoprotein (NP) and CD137L (4-1BBL) (Ad-NP-4-1BBL), I find that this supraphysiological administration of 4-1BB signals induces a robust long-lived circulating effector memory (Tem) population and a persistent lung tissue-resident memory (Trm) population, providing protection against lethal heterotypic influenza challenge. Ad-NP-4-1BBL acts directly on 4-1BB expressed by CD8 T cells to induce this expansion, and accumulation of memory CD8 T cells in the lung is dependent on local immunization with both antigen and 4-1BBL, recruitment of circulating effector cells into the tissue, and mTOR signalling. Moreover, we find endogenous 4-1BB to be a critical regulator of effector CD8 T cell accumulation in the lung tissue after influenza infection, which correlates with Trm establishment. This implicates 4-1BB as a potent regulator of both local and systemic T cell responses to influenza and may be a potential therapeutic target in future vaccine design. On the other hand, CD30 has no discernable roles in CD4 or CD8 T cell responses during acute influenza or chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infections. Rather, CD30 regulates the age-dependent expansion of the T memory compartment, which may have implications for the role of CD30 in human lymphoproliferative diseases. Taken together, we have identified novel functions of two TNFR members in regulating T cell responses during infection and at steady state. A better understanding of the post-priming mechanisms of these molecules can provide insight into future clinical interventions for viral infection and cancer malignancies.Ph.D.2019-07-11 00:00:0