UC Irvine

CD8+ T cells are a critical component of adaptive immune responses, mediating the clearance of viral infections and cancers while providing long-term protection. In response to infection, CD8+ T cells enter a range of differentiation states dictated by antigen strength and other environmental cues. These extrinsic signals induce a network of transcriptional regulators that further specify the CD8+ T cell fate decision. The significant impact of extrinsic signals on the quality of T cell responses and the subtypes of T cells produced is highlighted by the drastic differences in phenotype and function of T cells arising during acute and chronic infections. During acute infections, antigen-specific CD8+ T cells differentiate into cytotoxic effector T cells that clear the infection before a small subset differentiate into memory T cells for long-lived immunity. These effector and memory T cell differentiation programs are altered during chronic viral infections and cancers due to persistent antigen stimulation, resulting in antigen-specific CD8+ T cells entering a state of exhaustion. Exhausted CD8+ T cells are dysfunctional compared to the effector and memory T cells that arise during acute infections, resulting in impaired immune responses to chronic infections and diminished long-term protection. As with effector and memory differentiation, exhaustion is accompanied by specific transcriptional and epigenetic programs that reinforce this terminal cell fate. However, the complete characterization of the cellular and molecular mechanisms underlying effector, memory, and exhausted CD8+ T cell differentiation are still unknown. We investigated the role of HMGB2, a chromatin modifier, on the transcriptional and epigenetic networks that modulate terminal differentiation of antigen-specific CD8+ T cells during acute and chronic infections. During acute LCMV Armstrong infection, we found HMGB2 was critical for the differentiation and maintenance of memory CD8+ T cells, and more specifically the central memory T cell (Tcm) subset. Tcm cells are critical for secondary immune responses to reinfections, and correspondingly, memory Hmgb2-/- CD8+ T cells were unable to mount a response to a secondary challenge. We showed that HMGB2 regulated the accessibility of memory and stem cell associated genes that were required for memory T cell differentiation and recall responses. We also found that HMGB2 expression was dispensable for effector CD8+ T cell responses, as WT and Hmgb2-/- CD8+ T cells had equivalent frequencies, numbers, and cytotoxic function during Arm infection. In contrast, we found a critical role for HMGB2 in the maintenance of exhausted CD8+ T cells during chronic LCMV Cl13 infection and cancer. We found that HMGB2 was required for the differentiation and survival of progenitor exhausted (Tpex) T cells, which are critical for seeding the exhausted T cell pool and re-expansion to immune checkpoint blockade therapies. Therefore, exhausted Hmgb2-/- CD8+ T cells were lost during Cl13 infection and within melanoma tumors, with an inability to re-expand upon secondary acute infection. We found HMGB2 regulated the accessibility and expression of Tpex associated genes, while inhibiting the accessibility and expression of genes associated with terminally exhausted (Tex) T cells. The decline of these more terminally exhausted Hmgb2-/- CD8+ T cells resulted in diminished viral and tumor control using both in vivo adoptive transfer T cell models and Hmgb2-/- mice. Together, this dissertation details the critical role for HMGB2 in regulating the transcriptional and epigenetic networks of memory and exhausted CD8+ T cell differentiation. This work is an important contribution to our current understanding of CD8+ T cell fate decisions during acute and chronic infections, with various implications for vaccination and immunotherapeutic strategies.