(IL-)2 be or not to be? Immunological T follicular helper (TFH) cells are a subpopulation of CD4+ T cells that support B cell antibody production and the establishment of B cell memory. By contrast, non-TFH cells orchestrate enhanced innate immune cell functions at sites of pathogen encounter. The factors underlying differentiation into a TFH or non-TFH cell remain poorly understood, though there is evidence to suggest that the T cell growth factor interleukin-2 (IL-2) may play a role. Using IL-2 reporter mice, DiToro et al. show that naïve CD4+ T cells that produce IL-2 are fated to become TFH cells, whereas nonproducers, which receive IL-2, become non-TFH cells. The CD4+ T cell–fate decision was linked to T cell receptor strength—only those naïve CD4+ T cells that received the highest T cell receptor signals were able to produce IL-2. Science, this issue p. eaao2933 Expression of the cytokine IL-2 is linked with cell fate choice in immunological T cells. INTRODUCTION The adaptive immune system has evolved to mount different types of responses that are matched to the type of invading pathogen. For CD4+ T cells, this is predicated on the multipotentiality of clonally restricted naïve T cells, which differentiate into distinct subsets of effector T cells contingent on recognition of cognate antigen and cytokine cues from cells of the innate immune system. There are two broad divisions of effector CD4+ T cells: T follicular helper (TFH) cells, which are programmed to interact with B cells within lymphoid tissues to support production of high-affinity, class-switched antibodies, and non-TFH effector cells, including T helper 1 (TH1), TH2, and TH17 cells, which are programmed to egress from lymphoid tissues to orchestrate heightened innate immune cell function at sites of pathogen entry. The mechanisms controlling bifurcation into TFH versus non-TFH effector cell pathways are incompletely understood. RATIONALE An impediment to understanding mechanisms controlling TFH–non-TFH cell divergence is an absence of early markers to define cells destined for these alternative fates. Unlike effector CD4+ T cells, which produce a diversity of cytokines that define their phenotype and function, naïve CD4+ T cells are largely limited to the rapid production of interleukin-2 (IL-2) when activated by antigen. IL-2 is only produced by a subset of activated naïve T cells, suggesting a possible relationship between IL-2 production and effector cell fate determination. To explore this, we developed two IL-2 reporter mice strains with complementary features that enabled the tracking and deletion of T cells on the basis of differential IL-2 expression. This allowed us to determine whether naïve T cells that do, or do not, produce IL-2 are biased in their developmental programming and, if so, how. RESULTS RNA sequencing of naïve T cells sorted on the basis of IL-2 reporter expression identified cosegregation of transcripts encoding IL-2 and Bcl6—the signature transcription factor of TFH cells. Conversely, IL-2–negative (IL-2–) cells preferentially expressed the gene Prdm1, which encodes the transcriptional repressor Blimp1. Blimp1, in turn, antagonizes Bcl6 and the TFH developmental program. This suggested that IL-2 producers give rise to TFH cells, whereas IL-2 nonproducers give rise to non-TFH effector cells. Moreover, the fact that IL-2 receptor signaling induces expression of Prdm1 via Stat5 suggested that IL-2 producers resisted IL-2 signaling and activated IL-2 signaling in nonproducers in trans. Indeed, in vivo studies established that IL-2 signaling was mostly paracrine and that depletion of IL-2–producing cells selectively impaired TFH cell development. Finally, IL-2 expression was limited to a subset of naïve T cells that received the strongest T cell receptor (TCR) signals, establishing a link between TCR signal strength, IL-2 production, and TFH versus non-TFH differentiation. CONCLUSION This study provides new insights into the mechanisms that control early bifurcation of CD4+ T cells into TFH and non-TFH effectors. Naïve T cells that receive differing strengths of TCR signals stratify into those that exceed a threshold predisposing them to IL-2 production and early TFH commitment and those that do not express IL-2 yet receive IL-2 signaling, which reinforces non-TFH effector commitment. IL-2–producing CD4+ T cells become TFH cells, whereas IL-2 nonproducers become non-TFH cells. (Left) Strong TCR signaling via an antigen presenting cell induces Il2 and Bcl6 gene expression (red pathway); weaker signaling induces expression of non-TFH genes (blue pathway), including Prdm1 and S1pr1, which encodes the S1P receptor S1PR1. Bcl6+ cells (red) secrete IL-2 in trans to T regulatory (Treg) cells (yellow) and recently activated IL-2– cells (blue), up-regulating IL-2 receptor IL2rα and reinforcing Prdm1. (Top right) Bcl6+ cells engage cognate B cells (green) and migrate to germinal centers (GCs); Bcl6+ TFH cells mature into GC-TFH cells. (Bottom right) Prdm1+ cells migrate to efferent lymphatics and mature into non-TFH effectors in nonlymphoid tissues. MHCII, major histocompatibility complex class II; ICOS, inducible costimulator; CXCR5, a receptor for chemokine CXCL13. In response to infection, naïve CD4+ T cells differentiate into two subpopulations: T follicular helper (TFH) cells, which support B cell antibody production, and non-TFH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4+ T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become TFH cells, delivered IL-2 to nonproducers destined to become non-TFH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.

中文翻译：

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不同的 IL-2 表达定义了滤泡与非滤泡辅助 T 细胞的发育命运

(IL-)2 是还是不是？免疫性 T 滤泡辅助 (TFH) 细胞是 CD4+ T 细胞的一个亚群，支持 B 细胞抗体的产生和 B 细胞记忆的建立。相比之下，非 TFH 细胞在病原体遭遇部位协调增强的先天免疫细胞功能。分化为 TFH 或非 TFH 细胞的潜在因素仍然知之甚少，尽管有证据表明 T 细胞生长因子白细胞介素 2 (IL-2) 可能起作用。DiToro 等人使用 IL-2 报告小鼠。表明产生 IL-2 的幼稚 CD4+ T 细胞注定要成为 TFH 细胞，而接受 IL-2 的非生产者则成为非 TFH 细胞。CD4+ T 细胞命运的决定与 T 细胞受体强度有关——只有那些接受最高 T 细胞受体信号的幼稚 CD4+ T 细胞才能产生 IL-2。科学，这个问题 eaao2933 细胞因子 IL-2 的表达与免疫 T 细胞中的细胞命运选择有关。引言 适应性免疫系统已经进化到可以产生与入侵病原体类型相匹配的不同类型的反应。对于 CD4+ T 细胞，这是基于克隆限制性幼稚 T 细胞的多能性，根据先天免疫系统细胞的同源抗原和细胞因子线索的识别，这些 T 细胞分化为不同的效应 T 细胞亚群。效应 CD4+ T 细胞有两大类：T 滤泡辅助 (TFH) 细胞，它们被编程为与淋巴组织内的 B 细胞相互作用，以支持产生高亲和力、类别转换的抗体和非 TFH 效应细胞，包括 T 辅助 1 (TH1)、TH2 和 TH17 细胞，它们被编程为从淋巴组织流出，以在病原体进入部位协调增强的先天免疫细胞功能。控制分叉成 TFH 与非 TFH 效应细胞通路的机制尚不完全清楚。基本原理 理解控制 TFH-非 TFH 细胞分化机制的一个障碍是缺乏早期标志物来定义注定这些替代命运的细胞。与产生多种细胞因子的效应 CD4+ T 细胞不同，CD4+ T 细胞在被抗原激活时主要限于快速产生白细胞介素 2 (IL-2)。IL-2 仅由一部分活化的幼稚 T 细胞产生，这表明 IL-2 的产生与效应细胞命运决定之间可能存在关系。为了探索这一点，我们开发了两种具有互补特征的 IL-2 报告小鼠品系，能够根据不同的 IL-2 表达跟踪和删除 T 细胞。这使我们能够确定产生或不产生 IL-2 的幼稚 T 细胞是否在其发育程序中存在偏见，如果是，则如何。结果 根据 IL-2 报告基因表达分选的幼稚 T 细胞的 RNA 测序鉴定了编码 IL-2 和 Bcl6（TFH 细胞的标志性转录因子）的转录本的共分离。相反，IL-2 阴性 (IL-2-) 细胞优先表达基因 Prdm1，该基因编码转录抑制因子 Blimp1。反过来，Blimp1 会对抗 Bcl6 和 TFH 发育程序。这表明 IL-2 生产者产生 TFH 细胞，而 IL-2 非生产者产生非 TFH 效应细胞。而且，IL-2 受体信号通过 Stat5 诱导 Prdm1 表达的事实表明，IL-2 生产者在反式中抵抗 IL-2 信号并激活 IL-2 信号。事实上，体内研究证实 IL-2 信号传导主要是旁分泌的，并且产生 IL-2 的细胞的消耗选择性地损害了 TFH 细胞的发育。最后，IL-2 表达仅限于接受最强 T 细胞受体 (TCR) 信号的幼稚 T 细胞亚群，从而在 TCR 信号强度、IL-2 产生和 TFH 与非 TFH 分化之间建立联系。结论 本研究为控制 CD4+ T 细胞早期分叉为 TFH 和非 TFH 效应子的机制提供了新的见解。接受不同强度 TCR 信号的幼稚 T 细胞分层为那些超过阈值的细胞，使它们易于产生 IL-2 和早期 TFH 承诺，以及那些不表达 IL-2 但接收 IL-2 信号的细胞，这增强了非 TFH 效应子承诺。产生 IL-2 的 CD4+ T 细胞变成 TFH 细胞，而非产生 IL-2 的 CD4+ T 细胞变成非 TFH 细胞。（左）通过抗原呈递细胞的强 TCR 信号诱导 Il2 和 Bcl6 基因表达（红色通路）；较弱的信号传导诱导非 TFH 基因（蓝色通路）的表达，包括编码 S1P 受体 S1PR1 的 Prdm1 和 S1pr1。Bcl6+ 细胞（红色）向 T 调节（Treg）细胞（黄色）和最近激活的 IL-2– 细胞（蓝色）分泌 IL-2，上调 IL-2 受体 IL2rα 并增强 Prdm1。（右上）Bcl6+ 细胞与同源 B 细胞（绿色）结合并迁移到生发中心 (GC)；Bcl6+ TFH 细胞成熟为 GC-TFH 细胞。（右下）Prdm1+ 细胞迁移到传出淋巴管并成熟为非淋巴组织中的非 TFH 效应器。MHCII，主要组织相容性复合体 II 类；ICOS，可诱导共刺激器；CXCR5，趋化因子 CXCL13 的受体。为应对感染，幼稚 CD4+ T 细胞分化为两个亚群：T 滤泡辅助 (TFH) 细胞，支持 B 细胞抗体的产生，以及非 TFH 细胞，其增强先天免疫细胞的功能。白细胞介素 2 (IL-2) 是幼稚 T 细胞产生的主要细胞因子，在这些群体的发育分化中起着重要作用。然而，IL-2 产生和命运决定之间的关系仍不清楚。使用记者老鼠，我们发现幼稚 CD4+ T 细胞对 IL-2 的不同产生定义了具有不同免疫功能的前体。注定要成为 TFH 细胞的 IL-2 生产者将 IL-2 传递给注定要成为非 TFH 细胞的非生产者。由于 IL-2 的产生仅限于接受最强 T 细胞受体 (TCR) 信号的细胞，因此已经建立了 TCR 信号强度、IL-2 产生和 T 细胞命运决定之间的直接联系。