| Naive CD4+ and CD8+ T cells reside in the immune periphery poised for the recognition of foreign antigens. Upon T cell receptor engagement, these progenitors undergo an extensive terminal differentiation process that incorporates numerous stimuli and represents a unique model of lineage commitment. The CD4+ T cell population develops into one of two subsets, Th1 and Th2, characterized by discrete cytokine secretion profiles. Th1 cells direct responses against intracellular pathogens, while the Th2 cell mediates antibody class switching and clearance of extracellular microbes. Similarly, the antigen inexperienced CD8+ T cell employs a genetic remodeling program resulting in an effector pool capable of rapid cytokine production and lysis of infected cells. Tissue restricted transcription factors have proven fundamental mediators of effector T cell fate determination.; A member of the highly conserved T-box family, T-bet was originally cloned and characterized as a Th1 specific transcription factor responsible for driving IFN-gamma production and enforcing Th1 development, while inhibiting the opposing Th2 pathway. Using mice genetically deficient of T-bet, we demonstrated that T-bet is required for the generation of a Th1 response against protein immunization and the intracellular protozoan Leishmania major. While T-bet was clearly required for NK and CD4+ T cell effector functions, T-bet-/- CD8+ T cells exhibited normal IFN-gamma production and cytolytic activity following polyclonal activation.; We sought to determine if Th1 differentiating cytokines were capable of promoting T-bet expression in the developing Th1 cell. We found that the IFN-gamma/STAT1 pathway, in combination with antigenic stimulation, rapidly induces T-bet. Parallel analysis of T-bet, STAT1 and STAT4 deficient T cells illustrated the requirement for STAT1 and T-bet during the initial phases of Th1 commitment, while suggesting that STAT4 is fundamental to subsequently stabilize the phenotype.; To elucidate a function for T-bet in CD8+ T cells we generated T-bet-/- mice on the MHC class I restricted OT-I TCR transgenic background. Surprisingly, this antigen specific system revealed that effector CD8+ CTL differentiation also requires T-bet. In the absence of T-bet, OT-I CD8+ T cells fail to acquire an effector surface marker phenotype, are impaired in the production of IFN-gamma, and exhibit diminished cytolysis. Furthermore, T-bet-/- mice are unable to mount a productive CD8+ response against viral infection. |
