Immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor CD8 T cells, which rapidly regenerate effector and memory cells during recurrent infection. The identification of factors and pathways involved in CD8 T cell differentiation is of obvious importance to improve vaccination strategies. Here, we show that mice lacking T cell factor 1 (Tcf-1), a nuclear effector of the canonical Wingless/Integration 1 (Wnt) signaling pathway, mount normal effector and effector memory CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV). However, Tcf-1-deficient CD8 T cells are selectively impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection. Tcf-1-deficient mice essentially lack CD8 memory precursor T cells, which is evident already at the peak of the primary response, suggesting that Tcf-1 programs CD8 memory cell fate. The function of Tcf-1 to establish CD8 T cell memory is dependent on the catenin-binding domain in Tcf-1 and requires the Tcf-1 coactivators and Wnt signaling intermediates β-catenin and γ-catenin. These findings demonstrate that the canonical Wnt signaling pathway plays an essential role for CD8 central memory T cell differentiation under physiological conditions in vivo. They raise the possibility that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or for therapies designed to promote sustained cytotoxic CD8 T cell responses against tumors.

The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either ␤-catenin or ␥-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of ␤- IntroductionThe function and the hierarchical organization of the hematopoietic system depend on the unique ability of rare hematopoietic stem cells (HSCs) to self-renew and to give rise to committed progenitors, which will generate all blood cell lineages. Our understanding of the control mechanisms, which govern the balance of proliferation and differentiation of HSCs, is crucial for the development of therapies in areas such as bone marrow transplantation and the treatment of leukemia.The canonical Wnt signaling pathway plays a key role in stem-cell maintenance, expansion of committed progenitor cells, and control of lineage decisions in a variety of tissues, including the hematopoietic system. 1 ␤-Catenin is the central molecule in the canonical Wnt signaling pathway, which is tightly regulated at the level of protein stability. ␤-Catenin transmits the Wnt signal into the nucleus, where it acts as transcriptional coactivator by binding to members of the lymphoid enhancer factor/T cell factor (LEF/TCF) family of transcription factors. The related molecule ␥-catenin/plakoglobin can fulfill similar functions and activate target genes on Wnt signaling. 2 Deregulation of canonical Wnt signaling by aberrant stabilization of ␤-catenin is linked to a range of diseases including various cancers, whereas ectopic expression of ␥-catenin has been linked to acute myeloid leukemias. 3,4 Several reports have implicated Wnt signaling in HSC expansion and demonstrated responsiveness of HSCs to Wnt signals. 5,6 Conversely, deletion of Wnt genes or the Wnt receptor Fzd9 affects T-and/or B-cell development 7,8 and transgenic or retroviral expression of inhibitors of canonical Wnt signaling such as axin or dkk1 further indicated an important function of this pathway in hematopoiesis and thymopoiesis. 5,9,10 Individual gene ablations of LEF-1 and TCF-1 transcription factors displayed phenotypes in B-, T-, and NK-cell development. 11-13 TCF-1 deficiency resulted in incomplete blocks within the CD4 Ϫ CD8 Ϫ (DN) compartment of early thymocyte development and at the transition from immature single positive (ISP) to the CD4 ϩ CD8 ϩ (DP) stage. 11,14-16 LEF-1-deficiency aggravated the phenotype of mice with a hypomorphic TCF-1 allele, 17 demonstrating that the 2 factors play to some degree redundant functions during T-cell development. However, a complete block of Wnt signaling in the hematopoietic system has not been analyzed and results obtained by individual gene ablations of the 2 known signal transmitters ␤-and ␥-catenin have thus far failed to support a critical role of this pathway in hematopoiesis. 16,18,19 Strikingly, a genetic complementati...

alphabeta and gammadelta T cells originate from a common, multipotential precursor population in the thymus, but the molecular mechanisms regulating this lineage-fate decision are unknown. We have identified Sox13 as a gammadelta-specific gene in the immune system. Using Sox13 transgenic mice, we showed that this transcription factor promotes gammadelta T cell development while opposing alphabeta T cell differentiation. Conversely, mice deficient in Sox13 expression exhibited impaired development of gammadelta T cells but not alphabeta T cells. One mechanism of SOX13 function is the inhibition of signaling by the developmentally important Wnt/T cell factor (TCF) pathway. Our data thus reveal a dominant pathway regulating the developmental fate of these two lineages of T lymphocytes.