Smad4 represses the generation of memory-precursor effector T cells but is required for the differentiation of central memory T cells

Abstract The transcriptional regulation underlying the differentiation of CD8 + effector and memory T cells remains elusive. Here, we show that 18-month-old mice lacking the transcription factor Smad4 (homolog 4 of mothers against decapentaplegic, Drosophila ), a key intracellular signaling effector for the TGF- β superfamily, in T cells exhibited lower percentages of CD44 hi CD8 + T cells. To explore the role of Smad4 in the activation/memory of CD8 + T cells, 6- to 8-week-old mice with or without Smad4 in T cells were challenged with Listeria monocytogenes . Smad4 deficiency did not affect antigen-specific CD8 + T-cell expansion but led to partially impaired cytotoxic function. Less short-lived effector T cells but more memory-precursor effector T cells were generated in the absence of Smad4. Despite that, Smad4 deficiency led to reduced memory CD8 + T-cell responses. Further exploration revealed that the generation of central memory T cells was impaired in the absence of Smad4 and the cells showed survival issue. In mechanism, Smad4 deficiency led to aberrant transcriptional programs in antigen-specific CD8 + T cells. These findings demonstrated an essential role of Smad4 in the control of effector and memory CD8 + T-cell responses to infection.