The transcriptional coregulator Prdm16 drives effector and memory T cell accumulation during respiratory influenza infection
Year: 2026
Type: dissertation
Abstract: Effective antiviral immunity requires coordinated expansion and persistence of CD8⁺ T cells. Costimulatory signaling through TNF receptor superfamily members, such as 4-1BB, plays a central role in sustaining protective T cell responses, particularly within non-lymphoid tissues; however, the downstream mechanisms that support T cell accumulation and long-term memory remain incompletely understood. This thesis investigates the role of the transcriptional coregulator PR domain containing 16 (Prdm16) as a downstream mediator of T cell-intrinsic 4-1BB signaling during acute respiratory influenza A virus infection. Prdm16 was identified as one of the most significantly regulated genes downstream of 4-1BB signaling in T cells in the lung during IAV infection, prompting an analysis of its role in T cell responses to influenza A virus. Genomic deletion and overexpression of Prdm16 studies revealed that Prdm16 is necessary to enhance the accumulation of antigen-specific effector and memory CD8+ T cells, with particularly pronounced effects on lung resident memory populations. Mechanistically, Prdm16 deficiency resulted in only modest reductions in post-priming proliferation. Instead, integrated bulk RNA sequencing, single-nuclei RNA sequencing, and single-nuclei chromatin accessibility analyses showed that Prdm16 deficiency impairs the expression of Pink1, an important mitophagy regulator. Furthermore, Prdm16 overexpression was associated with altered mitochondrial ultrastructure, characterized by more compact cristae, a feature previously linked to enhanced respiratory efficiency. In parallel, Prdm16 repressed expression of the inhibitory signaling molecule, Herpes Virus Entry Mediator (HVEM), suggesting that Prdm16 may also enhance T cell accumulation by limiting inhibitory signaling thresholds. Single-nuclei transcriptional analyses further uncovered a prominent Prdm16-dependent cellular state characterized by high translational and mitochondrial activity. This population lacked defining surface markers and appeared to represent a dynamic cellular state rather than a discrete subset, highlighting an unanticipated dimension of T cell regulation during antiviral responses. Together, this thesis identifies a 4-1BB-Prdm16 axis that promotes CD8⁺ T cell accumulation and memory formation during viral infection through integrated regulation of mitochondrial fitness, transcriptional programs, and inhibitory signaling. These findings expand current models of T cell co-stimulation and provide new insight into how tissue-localized signals shape durable antiviral immunity.
Source: TSpace (University of Toronto)
Author: Lee, Seungwoo
Institution: University of Toronto
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204014105