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 CD44hiCD8+ 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.
Highlights
Cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1) and low levels of IL-7 receptor-α (CD127) represent terminally differentiated, short-lived effector T cells (SLEC), whereas KLRG1lowCD127hi CD8+ T cells have a greater potential to enter into the memory pool.[3,4]
Specific inactivation of Smad[4] in T cells was achieved by crossing mice homozygous for a Smad[4] conditional allele (Smad4co/co)[14,15] with mice expressing a transgene encoding Cre recombinase driven by the lymphocyte-specific protein tyrosine kinase (Lck) proximal promoter.[16]
We found that the frequencies of Kb-ova+CD8+ splenic T cells originating from the Smad4co/co;Lck-Cre bone marrow were lower than those of Smad4co/co counterparts in the same recipients 35 days after primary infection (Figure 5d and Supplementary Figure S9)
Summary
Cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1) and low levels of IL-7 receptor-α (CD127) represent terminally differentiated, short-lived effector T cells (SLEC), whereas KLRG1lowCD127hi CD8+ T cells have a greater potential to enter into the memory pool.[3,4] In response to antigen restimulation, memory CD8+ T cells rapidly proliferate and differentiate into cytolytic T lymphocytes that confer enhanced protection against intracellular pathogens. 6 (Bcl6), and T-cell factor 7 (Tcf[7], known as Tcf[1], downstream transcription factor of the Wnt pathway) are required for important aspects of memory CD8+ T-cell generation.[5,7,8,9] In addition, B lymphocyte-induced maturation protein 1 (Blimp[1], encoded by Prdm1) is essential for the differentiation of short-lived cytotoxic effector T cells and memory responses.[10,11] A recent study based on highresolution microarray analyses has suggested that many other transcription factors are involved in these cell-fate decisions.[12] Surprisingly, Smad[4] (homolog 4 of mothers against decapentaplegic, Drosophila), a key intracellular signaling effector for the TGF-β superfamily, has been predicted as an activator.[12,13] it is of importance to identify the role of Smad[4] in the differentiation of CD8+ effector and memory T cells. We report that Smad[4] is required for the differentiation of effector CD8+ T cells and memory responses
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