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

다국어 초록 (Multilingual Abstract)

<▼1><P>Virus infections induce CD8<SUP>+</SUP> 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<SUP>+</SUP> T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8<SUP>+</SUP> T cells. After acute virus infection, CD8<SUP>+</SUP> T cells deficient in ZBTB32 showed enhanced virus-specific CD8<SUP>+</SUP> 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<SUP>+</SUP> T cell responses in the absence of ZBTB32 was catastrophic, as <I>Zbtb32</I><SUP><I>-/-</I></SUP> 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<SUP>+</SUP> T cell activation, bound to each other, and cooperatively regulated Blimp-1 target genes <I>Eomes</I> and <I>Cd27</I>. These findings demonstrate that ZBTB32 is a key transcription factor in CD8<SUP>+</SUP> effector T cells that is required for the balanced regulation of effector versus memory responses to infection.</P></▼1><▼2><P><B>Author summary</B></P><P>CD8<SUP>+</SUP> T lymphocytes are essential for immune protection against viruses. In response to an infection, these cells are activated, proliferate, and generate antiviral effector cells that eradicate the infection. Following this, the majority of these effector cells die, leaving a small subset of long-lived virus-specific memory T cells. Our study identifies a transcription factor, ZBTB32, that is required for the regulation of CD8<SUP>+</SUP> T cell responses. In its absence, antiviral CD8<SUP>+</SUP> T cell numbers increase to abnormally high levels, and generate an overabundance of memory T cells. When this dysregulated response occurs following infection with a virus that cannot be rapidly eliminated by the immune system, the infected animals die from immune-mediated tissue damage, indicating the importance of this pathway.</P></▼2>