Abstract
Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation. The dysregulation of CD8+ T cell responses in the absence of ZBTB32 was catastrophic, as Zbtb32-/- mice succumbed to a systemic viral infection and showed evidence of severe lung pathology. We found that ZBTB32 and Blimp-1 were co-expressed following CD8+ T cell activation, bound to each other, and cooperatively regulated Blimp-1 target genes Eomes and Cd27. These findings demonstrate that ZBTB32 is a key transcription factor in CD8+ effector T cells that is required for the balanced regulation of effector versus memory responses to infection.
Highlights
The anti-viral CD8+ T cell response has been the topic of intense investigation over recent years, beginning with early ground-breaking studies demonstrating that, at early times postinfection, effector cells destined to die could be distinguished from those destined to populate the long-lived memory pool [1]
We found that mice deficient in Zbtb32 generated an enhanced antiviral CD8+ T cell response during acute virus infection and had increased memory CD8+ T cell populations; the sustained expression of Zbtb32 in virus-specific CD8+ T cells dampened the anti-viral T cell response
We examined the cytokines involved in the induction of Zbtb32 mRNA
Summary
The anti-viral CD8+ T cell response has been the topic of intense investigation over recent years, beginning with early ground-breaking studies demonstrating that, at early times postinfection, effector cells destined to die could be distinguished from those destined to populate the long-lived memory pool [1]. Molecular analysis of these subsets has revealed complex networks of transcription factors regulating the numbers, the phenotypes, and the survival potential of antiviral CD8+ T cells in models of both acute and chronic infections [2,3,4]. Single-cell RNA-seq data have elaborated on these findings, identifying subpopulations of activated CD8+ T cells that show effector-like and memory-like gene expression profiles that can be seen as early as the first cell division [7]
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