Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory

by Hyun Mu Shin, Varun N. Kapoor, Gwanghun Kim, Peng Li, Hang-Rae Kim, M. Suresh, Susan M. Kaech, E. John Wherry, Liisa K. Selin, Warren J. Leonard, Raymond M. Welsh, Leslie J. Berg

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.

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