The Role of TNFR Family Members, TNFR2 and CD30, in the T cell Response Against Viral Infection

TNFR family members tightly regulate the threshold, magnitude and duration of T cell responses against respiratory viral infections. In this thesis, I examine the role of two TNFR family members, TNFR2 and CD30, in the CD8 and CD4 T cell responses against influenza virus. Therapeutic blockade of TNF is the gold standard treatment for certain chronic inflammatory diseases, consistent with the key role of TNF in many dysregulated inflammatory responses. TNF is produced by many cell types and is also involved in anti-viral immunity. In order to address the role of intrinsic TNF/TNFR2 interactions in CD8 T cell responses against respiratory influenza infection in mice, we used an adoptive transfer model in which only the transferred T cells lack TNF or TNFR2. During mild influenza infection, the capacity of the antigen-specific CD8 T cells to produce TNF increases throughout the infection, beyond the time of viral clearance. Autocrine TNF/TNFR2 interactions are dispensable for the initial expansion of the CD8 T cells, but potentiate contraction of the response in the lung, thus limiting a potentially damaging and excessive CD8 T cell response. However, peak CD8 T cell effector functions are enhanced by intrinsic TNF/TNFR2 interactions, illustrating a complex dual role for TNF in fine-tuning the adaptive immune response to influenza infection. CD30 was originally discovered as a marker highly expressed on Reed-Sternberg cells of Hodgkin’s lymphoma, and is currently being explored as a target for cancer therapy in clinical trials. However, the role of CD30 in regulating T cells in response to viral infection is poorly understood. Therefore, we investigated whether CD8 and CD4 T cell responses against influenza infection involve CD30. During both mild and severe influenza infections, CD30 is dispensable for the accumulation of CD8 and CD4 T cells and their cytokine production. On the other hand, preliminary data suggest CD30 plays a more significant role during a persistent virus infection. In summary, the studies conducted in this thesis reveal divergent roles for TNFR family members in controlling T cell responses against viral infection.Ph