The evolving role of T-bet in resistance to infection

Abstract

The identification of T-bet as a key transcription factor associated with the development of IFNγ-producing CD4⁺ T cells predicted a crucial role for T-bet in cell-mediated immunity and in resistance to many intracellular infections. This idea was reinforced by initial reports showing that T-bet-deficient mice were more susceptible to pathogens that survived within the lysosomal system of macrophages. However, subsequent studies revealed IFNγ-dependent, T-bet-independent pathways of resistance to diverse classes of microorganisms that occupy other intracellular niches. Consequently, a more complex picture has emerged of how T-bet and the related transcription factor eomesodermin (EOMES) coordinate many facets of the immune response to bona fide pathogens as well as commensals. This article provides an overview of the discovery and evolutionary relationship between T-bet and EOMES and highlights the studies that have uncovered broader functions of T-bet in innate and adaptive immunity and in the development of the effector and memory T cell populations that mediate long-term resistance to infection.

Fig. 1 |. The induction and diverse target genes of T-bet.

a | T-bet is induced in T cells through signal transducer and activator of transcription 1 (STAT1) downstream of T cell receptor (TCR) signalling and/or signalling through IFNγR, IFNαR, IL-27R and IL-21R. T-bet is also induced through STAT4 downstream of signalling through IL-12R. b | After T-bet is induced, it binds to an array of genes that exert diverse functions in the cell including activation (via IFNγ, IL12Rβ2 and STAT1), cellular trafficking (via CC-chemokine ligand 3 (CCL3), CXC-chemokine receptor 3 (CXCR3), tyrosyl protein sulfotransferase 2 (TPST2) and CD11a) and immune regulation (via IL-2, IL-4, IL-5 and RORγt). c | T-bet is induced in B cells through STAT1 after ligation of the B cell receptor (BCR) and/or IFNγR. T-bet can also be induced through MYD88 downstream of Toll-like receptor 9 (TLR9) signalling. pSTAT, phosphorylated STAT. APC, antigen-presenting cell.

Fig. 2 |. Expression of T-bet is linked to T cell trafficking behaviour.

a | T-bet activation is associated with the increased expression of CD11a as well as the expression of enzymes that promote the glycosylation of P-selectin glycoprotein ligand 1 (PSGL1) and its binding to P-selectin, which is required for T cell adhesion to inflamed endothelium and migration into sites of inflammation. Within these tissues, T-bet-mediated expression of CXC-chemokine receptor 3 (CXCR3) enables T cells to respond to IFNγ-induced chemokines, such as CXC-chemokine ligand 9 (CXCL9) and CXCL10, and thus mediate local control of infections in tissues. b | The coordinated expression of T-bet by effector T cell and regulatory T (T_reg) cell populations would enable these cell types to respond to similar environmental signals and ensure that the regulatory mechanisms mediated by T_reg cells occur at sites of T helper 1 (T_H1) cell-like inflammation. Whether T-bet acts in concert with forkhead box P3 (FOXP3) to engage distinct regulatory mechanisms that are required to limit local inflammation is uncertain.

Fig. 3 |. T-bet in immunity to pathogens that occupy distinct intracellular niches.

a | Pathogens such as Leishmania major are specialized to survive and replicate inside the phagolysosomal system. Microbial antigens at these sites drive the development of MHC class II-restricted T-bet-dependent CD4⁺ T cells, and the production of IFNγ by these cells is the dominant pathway that mediates parasite control. b | The ability to escape from the phagolysosomal system into the cytosol of host cells provides a mechanism for Listeria monocytogenes to avoid killing, but in this compartment, bacterial antigens are readily presented to MHC class I-restricted CD8⁺ T cells. In addition, innate responses mediated by natural killer (NK) cells also contribute to the production of IFNγ. c | Toxoplasma gondii replicates in a unique parasitophorous vacuole that does not fuse with the lysosomal compartment but fully engages innate and adaptive production of IFNγ. While the ability to generate parasite-specific CD4⁺ T cells is partially dependent on T-bet, the magnitude of the NK cell and CD8⁺ cell response appears intact in the absence of T-bet.

Fig. 4 |. Differential expression and function of T-bet and EOMES during differentiation of effector and memory T cell subsets.

A primary immune challenge results in the activation and expansion of pathogen-specific CD8⁺ T cell populations that give rise to distinct populations of memory precursors as well as effector cells. The relative levels of T-bet and eomesodermin (EOMES) differ in these populations and may be influenced by levels of T cell receptor (TCR) engagement, the process of cell division and the inflammatory environment, factors which in turn influence the expression of surface molecules associated with distinct trafficking and effector functions. After resolution of infection, it is unclear how T-bet and EOMES influence memory responses to secondary challenges or, in the case of persistent infection, whether these transcription factors are required to maintain effective long-lived T cell responses. CX3CR1, CX3C-chemokine receptor 1; CXCR3, CXC-chemokine receptor 3; KLRG1, killer cell lectin-like receptor subfamily G member 1.