Transcription factors come of age in lymphoma immunophenotyping: a (T-)bet that has paid off.

In this issue of the Journal, Dorfman and colleagues1 describe the usefulness of T-bet as a marker for specific subtypes of B-cell lymphoma. T-bet originally was identified as a T-box family transcription factor that dominantly programs CD4 and CD8 T-cell development along Th1 and Tc1 pathways, respectively.2 It accomplished this impressive task in part through the coordinated transcriptional activation of the IFN-γ (interferon-γ) gene and repression of the IL-4 (interleukin-4) gene. The clinical importance of T-bet emerged in studies of T-bet knockout mice, which showed airway abnormalities remarkably similar to those in human asthma; furthermore, airway samples from human patients with chronic asthma showed marked reduction of T-bet expression within CD4+ T cells.3 By contrast, overexpression of T-bet occurred in lamina propria T cells of colonic biopsy specimens from patients with Crohn disease, a causal role for which was supported by a murine model system of enforced T-bet expression in CD4+ T cells.4 Thus either overexpression or underexpression of T-bet in T cells might contribute to the development of certain types of human inflammatory or autoimmune disease, presumably through the dysregulation of the balance of Th1 and Th2 cells. Initial studies of human tumors logically focused on Tcell lymphomas, in which T-bet expression occurred in a high percentage of angioimmunoblastic, lymphoepithelioid, and Th1 T cell–like lymphomas. Cases with no or low-incidence expression included T-cell precursor (0%), anaplastic large cell (25%), and Th2 T cell–like (18%) lymphomas.5 Strikingly little T-bet expression manifested in reactive tonsil or normal adult thymus. These results corroborated recent subtyping of peripheral T-cell lymphomas (PTCLs) by a panel of surface markers that assigned angioimmunoblastic lymphoma to Th1-like and anaplastic large cell lymphoma to Th2-like categories.6 Important questions for the future include how well T-bet expression can predict a Th1-like phenotype in PTCL and the prognostic relevance of T-bet expression as well as Th category. More basic questions include whether T-bet expression simply reflects the preexisting phenotype of the T cell destined for malignancy or whether T-bet expression itself might contribute in some way to the pathogenesis of cases of PTCL. In normal B cells, previous studies had shown minimal baseline expression but strong up-regulation in response to certain activating stimuli, eg, those that promote IFN-γ production2 and CpG-containing DNA.7 Again, the T-bet knockout mice shed light on function, showing a role in initiating immunoglobulin heavy chain (IgH) gene class switching, preferentially to IgG2A.8 This function is fascinating in the light of the absence of detectable T-bet expression in normal germinal centers, the usual site of class switching.5 Another consequence of loss of T-bet function in these studies was reduction in autoantibody production in the murine lupus model.8 This intriguing finding suggests that Tbet might promote development or activation of B-1 B cells and anticipates the findings in the present study in which Tbet was expressed frequently in cases of chronic lymphocytic leukemia (CLL),1 a malignancy of the human counterpart of the B-1 B cell (the CD5 B cell) and characterized by a propensity for autoantibody production. The present analysis of T-bet expression in a variety of human B-cell malignant neoplasms yielded novel and potentially useful results. T-bet expression occurred in all B-cell precursor malignant neoplasms (BCP-ALL), in stark contrast with the absence of T-bet expression in all Burkitt