Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation.

Central memory CD8+ T cells (Tcm) control systemic secondary infections and can protect from chronic infection and cancer as a result of their stem-cell-like capacity to expand, differentiate, and self-renew. Central memory is generally thought to emerge following pathogen clearance and to form based on the de-differentiation of cytolytic effector cells. Here, we uncovered rare effector-phase CD8+ T cells expressing high amounts of the transcription factor Tcf7 (Tcf1) that showed no evidence of prior cytolytic differentiation and that displayed key hallmarks of Tcm cells. These effector-phase Tcf7hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7hi cells and sustained the expression of conserved adult stem-cell genes that were critical for CD8+ T cell stemness. The discovery of stem-cell-like CD8+ T cells during the effector response to acute infection provides an opportunity to optimize Tcm cell formation by vaccination.

Emergence and fate of stem cell-like Tcf7+ CD8+ T cells during a primary immune response to viral infection.

In response to infection, naïve CD8+ T (TN) cells yield a large pool of short-lived terminal effector (TTE) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (TCM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like TCM cells arise by dedifferentiation from a subset of cytolytic TTE cells or whether priming generates stem-like cells capable of seeding the TCM compartment and, if so, when cytolytic TTE cells branch off. Here, we show that CD8+ T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs TN cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1+ cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1+ TCM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1+ cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a TTE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1+ relative to TCF1- cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default.

The Influence of Schmorl Nodes in Spinal Sagittal Balance in Young Adults.

Objectives The present study aims to characterize the spinal balance (SB) in young adults with Schmorl nodes (SN). Methods A cross-sectional study was conducted on a sample of 47 young adults. Lumbar magnetic resonance imaging (MRI) was used to divide the patients into an SN group and a control group. Standing full spine radiographs were used to compare the spinopelvic SB parameters between groups: sagittal vertical axis, thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Results The LL and SS values were significantly lower in patients with SN when compared with the control group (54.5° versus 64.3°; 36.2° versus 41.4°, respectively). No significant differences were observed for the other parameters. Significant correlations were found in both groups between LL and SS; PI and PT; and PI and SS. Conclusions Young adults with SN have associated SB modifications, particularly lower LL and SS values, when compared with a control group. This flatter profile resembles that observed in patients with lower back pain and early disc pathology. We believe that SNs are relevant clinical findings that should prompt the study of the SB of a patient, as it may uncover variations associated with early disc degeneration. Level of Evidence III.

Suppression of Tcf1 by Inflammatory Cytokines Facilitates Effector CD8 T Cell Differentiation.

The formation of central CD8 T cell memory in response to infection depends on the transcription factor Tcf1 (Tcf7). Tcf1 is expressed at high levels in naive CD8 T cells but downregulated in most CD8 T cells during effector differentiation. The relevance of Tcf1 downregulation for effector differentiation and the signals controlling Tcf1 expression have not been elucidated. Here, we show that systemic inflammatory signals downregulated Tcf1 in CD8 T cells during dendritic cell vaccination and bacterial infections. The suppressive effect was mediated by the inflammatory cytokine interleukin 12 (IL-12), which acted via STAT4 in CD8 T cells. IL-12-induced Tcf1 downregulation required cell cycling, occurred at the transcriptional level, and was prevented in part by inhibiting DNA methyltransferases. Absence of Tcf1 during T cell priming circumvented the need of systemic inflammation for effector differentiation. We conclude that silencing of Tcf1 by systemic inflammation facilitates effector CD8 T cell differentiation.

The Influence of Schmorl Nodes in Spinal Sagittal Balance in Young Adults / A Influência dos nódulos de Schmorl no equilíbrio sagital de adultos jovens

Abstract Objectives The present study aims to characterize the spinal balance (SB) in young adults with Schmorl nodes (SN). Methods A cross-sectional study was conducted on a sample of 47 young adults. Lumbar magnetic resonance imaging (MRI) was used to divide the patients into an SN group and a control group. Standing full spine radiographs were used to compare the spinopelvic SB parameters between groups: sagittal vertical axis, thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Results The LL and SS values were significantly lower in patients with SN when compared with the control group (54.5° versus 64.3°; 36.2° versus 41.4°, respectively). No significant differences were observed for the other parameters. Significant correlations were found in both groups between LL and SS; PI and PT; and PI and SS. Conclusions Young adults with SN have associated SB modifications, particularly lower LL and SS values, when compared with a control group. This flatter profile resembles that observed in patients with lower back pain and early disc pathology. We believe that SNs are relevant clinical findings that should prompt the study of the SB of a patient, as it may uncover variations associated with early disc degeneration. Level of Evidence III

Resumo Objetivos O presente estudo tem como objetivo caracterizar o equilíbrio sagital (SB, na sigla em inglês) espinhal em adultos jovens com nódulos de Schmorl (NS). Métodos Este é um estudo transversal de uma amostra composta por 47 adultos jovens. Ressonância magnética (RM) lombar foi usada para separar os pacientes em um grupo com NS e um grupo controle. Radiografias da coluna vertebral em pé foram usadas para comparar os parâmetros espinopélvicos do SB entre os grupos: eixo vertical sagital, cifose torácica, lordose lombar (LL), incidência pélvica (PI, na sigla em inglês), inclinação pélvica (PT, na sigla em inglês) e inclinação sacral (SS, na sigla em inglês). Resultados Os valores de LL e SS foram significativamente menores nos pacientes com NS em comparação com o grupo controle (54,5° versus 64,3°; 36,2° versus 41,4°, respectivamente). Não foram observadas diferenças significativas nos demais parâmetros. Os dois grupos apresentaram correlações significativas entre LL e SS, PI e PT e PI e SS. Conclusões Adultos jovens com NS apresentam modificações associadas ao SB, principalmente valores menores de LL e SS, em comparação com o grupo controle. Este perfil mais plano assemelha-se ao observado em pacientes com lombalgia e patologia discal em estágio inicial. Acreditamos que o NS seja um achado clínico relevante que deve levar ao estudo do SB de um paciente por poder revelar variações associadas aos primeiros estágios de degeneração discal. Nível de Evidência III

Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC).

The familial forms of non-medullary thyroid carcinoma (FNMTC) represent approximately 5 % of thyroid neoplasms. Nine FNMTC susceptibility loci have been mapped; however, only the DICER1 and SRGAP1 susceptibility genes have been identified. The transcription factors NKX2-1, FOXE1, PAX8, and HHEX are involved in the morphogenesis and differentiation of the thyroid. Recent studies have identified NKX2-1 germline mutations in FNMTC families. However, the role of high-penetrant FOXE1 variants in FNMTC etiology remains unclear. The aim of this study was to investigate the role of FOXE1 germline mutations in the pathogenesis of FNMTC. We searched for molecular changes in the FOXE1 gene in the probands from 60 Portuguese families with FNMTC. In this series, we identified nine polymorphisms and one variant (c.743C>G, p.A248G) which was not previously described. This variant, which involved an amino acid residue conserved in evolution, segregated with disease in one family, and was also detected in an apparently unrelated case of sporadic NMTC. Functional studies were performed using rat normal thyroid cells (PCCL3) clones and human papillary thyroid carcinoma cell line (TPC-1) pools, expressing the wild type and mutant (p.A248G) forms of FOXE1. In these experiments, we observed that the p.A248G variant promoted cell proliferation and migration, suggesting that it may be involved in thyroid tumorigenesis. Additionally, somatic p.V600E BRAF mutations were also detected in the thyroid tumors of two members of the family carrying the p.A248G variant. This study represents the first evidence of involvement of a germline FOXE1 rare variant in FNMTC etiology and suggests that mutations in MAPK pathway-related genes may contribute to tumor development in these familial cases.