Editorial: Not all roads to T cell memory go through STAT4 and T-bet.

The early immune response to infection is a carefully orchestrated sequence of events that suppresses early virus replication, while generating adaptive immune responses that not only help to control infection but also form long-lasting immune memory. Innate cell subsets express surface receptors that can sense components of some pathogens, and infected cells recognize infection through a variety of sensors, including TLRs and retinoic acid-inducible gene I-like receptors. Subsequently, infected cells express IFNs and other proinflammatory cytokines that act directly on T cells or on APCs, resulting in a wave of additional cytokine and costimulatory molecule signals. Some of these signals are transmitted through interactions between T cells and DCs (via costimulatory molecules, IL-12 and IL-18) and others relayed between T cells (IFNand IL-2). These interactions, together with TCR signals, guide the differentiation of antigen-specific T cells to cells that express certain effector cytokines or proteins involved in cytolysis. As effector cells proliferate and differentiate, they travel to different locations to carry out their effector functions, while a subset of cells avoids terminal differentiation and survives to populate the memory cell pool [1]. The earliest stages of T cell differentiation begin within a few days of infection, and the process is likely guided iteratively by the continued input of new combinations of cytokines as the infection progresses or is eliminated. Consequently, multiple T cell subsets evolve, each having distinct functional properties. Cytokines influence the proportion of CD8 T cells that become SLEC, which are prone to terminally differentiate, or MPEC, which have long-term survival potential as memory cells [1]. By comparison, various cytokines promote the differentiation of CD4 T cells into far more distinguishable lineages after virus infection, including Th1, Th2, TFH, and others. Each lineage preferentially localizes to T cell zones or B cell borders in lymphoid organs or circulates to peripheral sites of infection. The distinct CD4 T cell lineages establish memory, and each has well-defined functions that contribute to immune protection. Thus, the early cytokine milieu and antigen load have immediate and long-ranging effects on T cell differentiation and host protection. The cytokine signals are distilled to a complex set of transcription factors that vary in abundance in responding T cells. This information is refined further to decisions at the chromatin level that guide commitment into the distinct lineages (e.g., Th1 vs. TFH) and influence whether the cells terminally differentiate as effectors or progress on to memory. There is an ongoing effort to understand how cytokines and transcription factors impact effector functions and memory cell development. Such information could be used to better design vaccines that are tailored to improve immunity. For example, adjuvants could be designed that preferentially stimulate CD4 TFH cells when vigorous antibody responses are needed or preferentially induce CD4 Th1 cells when protective immunity centers on CD8 T cells or macrophage activation. IFNs and IL-12 are key players in effector and memory cell differentiation (Fig. 1). Type 1 or type 2 IFNs bind to IFNR or IFNR to activate STAT1-mediated signaling. In TCR-stimulated cells, such as during infection, IFNsignaling is redirected through STAT4 [2]. IFNsignals evoke different responses in T cells depending on variation in STAT abundance: IFNR-mediated signaling through STAT4 promotes IFNand T cell-proliferative responses to infection, whereas IFNR-directed signaling through STAT1 inhibits T cell proliferation [3]. STAT4 is also activated by IL-12 that is released from activated DCs in many infections. Thus, STAT4 plays a central role in translating IFN and IL-12 signals into T cell responses. One of the main consequences of STAT4 and STAT1 signaling following T cell exposure to IFNs or IL-12 is the induction of T-bet [4, 5]. The STAT4–T-bet pathway promotes IFNexpression from effector T cells and stimulates increased T cell expression of IL-12R and IL-18R. Thus, TCR stimulation, along with IFNs and IL-12, results in T cells that are receptive to additional proinflammatory cytokine signals, influencing the magnitude of the T cell response and the subsequent formation of memory [1, 6]. T-bet is thought to guide this process. Ectopic expression of T-bet directly influences the differentiation process of CD4 and