T-bet Transcendent: Unmasking the Faces of Multifarious Immunity

We dwell in an environment filled with germs of different sizes and lifestyles. In response, we have evolved a sophisticated system of host defense that can recognize nearly limitless antigenic shapes. We have also evolved the flexibility to combat the different evasion mechanisms of intruders with a suitably strategic counteroffensive. The way we eliminate intracellular pathogens, viruses, and cancer cells (type 1 immunity) is distinct from how we reject intestinal worms (type 2 immunity) or how we neutralize extracellular bacteria (type 17 or type 3 immunity). The Pillars of Immunology article featured in this issue by Szabo et al. (1) provided crucial insight into how a naive CD4⁺ T cell begets a distinct lineage of effector cells and, in so doing, identified the key transcription factor of type 1 immunity.

Understanding how we develop and deploy different forms of attack against microbes was a major preoccupation for contemporary immunology at the end of the 20th century. It was understood that humoral immunity and cell-mediated immunity were distinct and sometimes complementary immune functions (2). Investigation into the nature of the immune response decision turned toward the field of Th cell subset heterogeneity after the discovery that cloned, Ag-specific CD4⁺ T cells segregated into mutually exclusive patterns of helper function and cytokine secretion (3). The lynchpin of type 1 defense, CD4⁺ Th1 cells are capable of secreting IFN-γ, which, among other functions, instructs cells harboring an intracellular infection to produce reactive oxygen and nitrogen species that could eliminate their unwanted invasion.

The landmark study from Laurie Glimcher’s laboratory reported cloning and characterization of the master transcription factor of Th1 cells (1). The authors named the novel member of the T-box–containing transcription factor family “T-bet,” for T-box factor expressed in T cells. The effort, which has been recounted in an entertaining narrative by Dr. Glimcher (4), was spearheaded by a talented postdoctoral fellow, Susanne Szabo, who had studied IL-12 signaling in Th1 cells while she was a graduate student in Ken Murphy’s laboratory at Washington University.

From the early days of studying cloned CD4⁺ T cells (3), IL-2 was thought to be a Th1-specific cytokine, although now it is typically associated with naive and central memory T cells. The strategy employed by Szabo, Glimcher, and colleagues was to find factors that could transactivate the Il2 promoter, which T-bet apparently could do in the context of the yeast one-hybrid screen (1). When studied in the context of actual T cells, T-bet was later shown to be a repressor of Il2. Importantly, when genetically introduced into CD4⁺ T cells, T-bet was capable of inducing abundant expression of IFN-γ, the signature of Th1 cells, and repressing expression of IL-4, the signature of Th2 cells.

During the ensuing years, genetic, biochemical, and cell biological studies from the Glimcher laboratory and their collaborators have only amplified the importance of T-bet as the key upstream transcription factor of Th1 cells (5). T-bet imparts a Th1-specific gene expression program while repressing Th2 and Th17 genes. T-bet acts as a conventional transcriptional activator of some genes and a remodeler of heritable chromatin structure at other loci. T-bet informs Th1 cells on actions as wide-ranging as cytokine synthesis, tissue localization, restricted growth factor consumption, and terminal senescence.

Prior to the identification of T-bet, Th1 and Th2 differentiation was a problem largely understood as the sum of the cytokine signaling received by a naive T cell. The discoveries of T-bet (1) along with that of Gata-3 (6) and later retinoic acid–related orphan receptor γt (7) as the key upstream transcription factors of Th1, Th2, and Th17 cells, respectively, have been critical pieces of the puzzle for deciphering the signaling and transcriptional networks of T cell differentiation during the immune response. The identification of T-bet was a watershed moment for the field to begin understanding the issues of plasticity, flexibility, heritability, and reversibility of the distinct cell fates that are carved out of a common naive precursor.

The cloning and characterization of T-bet as the key transcription factor of CD4⁺ Th1 cells paved numerous other important paths of discovery (5). Subsequent findings by Dr. Glimcher’s laboratory and those of her colleagues concerning the roles of T-bet across numerous hematopoietic lineages helped solidify T-bet’s role as a key regulator of almost every facet of type 1 immunity. T-bet also plays critical roles in the development and/or function of CD8⁺ T cells, atypical T cell subsets, innate lymphoid cells (including NK cells), dendritic cells, and B cells. Not surprisingly, T-bet has been implicated in the pathogenesis of infectious, autoimmune, inflammatory, and neoplastic processes (5).

T-bet’s representation as the molecular signature of type 1 immune cells has been a beacon in the fog that helped lead us forward. Without T-bet, it seems unlikely we would have arrived at our current understanding of the modular nature of immune function and the appreciation that distinct modules transcend numerous interacting cell types (8–11). Like many great discoveries, the identification of T-bet as the key transcriptional regulator of Th1 cells continues to be an enduring gift to the field in many unexpected ways.