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 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.

SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral memory CD8 T cells

“…Krupple-like factor 2 play a central role in transcriptional regulation of CD62L during the CTL response(Takada et al, 2011). Since our data indicate that CD62L is regulated via SMAD4(Cao et al ., 2015; Hu et al ., 2015b), we used cultured CTLs to measure Sell (CD62L) and KLF2 transcripts after cytokine stimulation (Fig. 3H).…”

“…For these studies, Cre is expressed under the control of the distal Lck (dLck) promoter to induce DNA at a late stage during thymic development (ref). When we analyzed homing-receptors during IAV infection, we found that antiviral CTLs displayed very different phenotypes in the absence of either SMAD4 or TGFβRII (Cao et al ., 2015; Hu et al ., 2015a). Since SMAD4 and TGFβRII are components of an interconnected signaling network, we intercrossed S4KO and TR2KO mice to produce CTLs that lack both molecules (S4TR2-DKO).…”

“…Although many inflammatory mediators influence the fate decisions of activated CTLs, the mechanisms that coordinate changes homing receptor expression as CTLs respond to during infection are poorly understood. We previously found that a network of signaling pathways, that are controlled by members of the transforming growth family (TGF), alter the functional attributes of pathogen-specific CTLs during memory formation (Cao et al, 2015; Hu et al, 2015b). For the current study, we used additional stains of genetically- modified mice to further define how these important regulatory pathways influence genetic-programming of pathogen-specific CTLs.…”

Consequences of Mutations and Abnormal Expression of SMAD4 in Tumors and T Cells

“…Generation of memory-precursor of CD8 + T cells was controlled by SMAD4, and its deficiency weakens the response of memory CD8 + T cells, as their cytotoxic function is partially impaired. 86 During chronic viral infection, the CD8 + and CD4 + T cells are suppressed. The differentiation and accumulation of CD4 + T cells were required SMAD4.…”

Papel del TGF-beta en la inmunidad contra el rotavirus en el modelo múrido neonatal

“…SMAD4 es una proteína importante en la señalización intracelular de TGF por lo que se podría esperar que ratones con una inactivación específica de SMAD4 se asemejen a ratones con alteración en la señalización del TGF (69) Un estudio en ratones deficientes de SMAD4 mostró que en el bazo de estos hay una mayor proporción de LT CD8 MPEC en respuesta a la infección con LM, a diferencia de los ratones con expresión de SMAD4 normal (68). Sin embargo, pese al aumento de los LT CD8 MPEC totales, los LTCD8 específicos de la bacteria permanecieron en niveles comparables a los ratones no infectados 5 días después de una segunda infección, debido a que presentaron una sobrevida disminuida y por lo tanto la acumulación de MPEC no resultó en aumento de la memoria (69). Es desconocido si este mecanismo se puede aplicar a los LT CD4 MPEC, pero podría explicar por qué en nuestro estudio los ratones que recibieron anti-TGF presentaron frecuencias más altas de LT CD4 MPEC y a pesar de esto tuvieron una menor protección frente al reto con RV-EC en comparación con los grupos RRV-IC y RRV-aLAP.…”