The invariant TCR expressed by iNKT cells recognizes lipid antigens presented in the context of the MHC class I-like LDN-193189 molecule CD1d. Invariant NKT cells, which have been extensively studied in mice, are, comparatively, quite rare in humans. For example, in mice 30–40% of T cells in the liver are iNKT cells; in humans only,1% of hepatic T cells are iNKT cells. Our lab, and others, have shown that in mice, PLZF controls the development of essentially all of the innate-like features of NKT cells. For example, PLZF-deficient NKT cells do not acquire the typical “activated” phenotype characterized by high expression of CD44 and CD69. PLZF deficient NKT cells also do not constitutively express granzyme B or the mRNA transcript for IL-4 and fail to acquire the capacity to secrete multiple cytokines upon primary stimulation. Furthermore, the frequency of NKT cells is substantially reduced in PLZF-deficient mice and the cells accumulate in the lymph nodes and spleen rather than in the thymus and liver. Overall, the phenotype of PLZF-deficient NKT cells is highly reminiscent of naı¨ve, conventional CD4 T cells. In contrast, ectopic expression of PLZF in conventional T cells results in the acquisition of innate T cell-like characteristics such as an activated phenotype, the rapid secretion of Th1 and Th2 cytokines in response to an initial stimulus and homing to non-lymphoid tissues. Recent studies have shown that PLZF expression is not strictly limited to invariant NKT cells in mice, but can also be found in a specific subset of cd T cells that express a Vc1.1Vd6.3 TCR. This subset of “NKT” cd T cells functionally resemble invariant NKT cells in that they co-secrete both IFN-c and IL-4 upon primary activation. Importantly, PLZF has been shown to be required for the innate T cell-like characteristics of NKT cd T cells. These studies, together with the findings in NKT cells, highlight an essential and non-redundant role for PLZF in the development of innate T cell effector functions. In addition to directly controlling the function of the cells it is expressed within, PLZF impacts immune function in trans. Of great interest, studies show that the IL-4 produced by these PLZFexpressing cells profoundly alters the CD8 T cell compartment. In mice with an expanded PLZF-expressing T cell compartment, CD8 T cells were found to take on an innate-like phenotype, represented by increased expression of CD44, Eomes and an enhanced capacity to secrete IFN-c. Such mice also harbor increased numbers of germinal center B cells and high serum levels of IgE, in concordance with their heightened Th2 responses. These data show that innate-like T cells, such as NKT cells, have a broad impact on the immune response. The role of NKT cells in disease is complex and appears to be dependent on both the NKT cell subtype and the microenvironmental context. In mice, NKT cells have been shown to be important in the suppression of solid tumors as a consequence of interactions with dendritic cells and other lymphocytes. In contrast, the immunomodulatory activity of NKT cells can also influence the immune response against autoantigens.