This information is current as Innate CD 4 T Cells + and PLZF + of IL-4 A Transgenic TCR Directs the Development

MHC class II–expressing thymocytes can efficiently mediate positive selection of CD4 T cells in mice. Thymocyte-selected CD4 (T-CD4) T cells have an innate-like phenotype similar to invariant NKT cells. To investigate the development and function of T-CD4 T cells in-depth, we cloned TCR genes from T-CD4 T cells and generated transgenic mice. Remarkably, positive selection of T-CD4 TCR transgenic (T3) thymocytes occurred more efficiently when MHC class II was expressed by thymocytes than by thymic epithelial cells. Similar to polyclonal T-CD4 T cells and also invariant NKT cells, T3 CD4 T cell development is controlled by signaling lymphocyte activation molecule/signaling lymphocyte activation molecule–associated protein signaling, and the cells expressed both IL-4 and promyelocytic leukemia zinc finger (PLZF). Surprisingly, the selected T3 CD4 T cells were heterogeneous in that only half expressed IL-4 and only half expressed PLZF. IL-4– and PLZF-expressing cells were first found at the double-positive cell stage. Thus, the expression of IL-4 and PLZF seems to be determined by an unidentified event that occurs post-selection and is not solely dependent on TCR specificity or the selection process, per se. Taken together, our data show for the first time, to our knowledge, that the TCR specificity regulates but does not determine the development of innate CD4 T cells by thymocytes. D uring an adaptive immune response, naive T cells go through activation-induced differentiation and then subsequent activation prior to producing effector molecules. In contrast, innate T cells such as invariant NKT (iNKT), mucosal-associated invariant T cells, and intestinal CD8aa intraepithelial lymphocytes release effector cytokines immediately upon stimulation (1–3). In addition to these innate T cells, we have identified CD4 T cells with similar characteristics (4). Unlike conventional CD4 T cells, which are selected by thymic epithelial cells, innate CD4 T cells are selected by MHC class II–expressing thymocytes (5, 6). To differentiate these two CD4 T cell populations, we named them epithelial cell-selected CD4 (E-CD4) and thymocyte-selected CD4 (T-CD4) T cells to reflect the selecting cell type of each. T-CD4 T cells show an effector/memory-like phenotype and readily produce effector cytokines upon stimulation (4, 7). T-CD4 T cells were shown to inhibit airway inflammation (4) and also suppressed Ag-specific responses of CD8 or CD4 T cells during bacterial infections indicating an immune-suppressive function for T-CD4 T cells (8). Innate T-CD4 T cells are also reported to be present in humans (9). Development of T-CD4 T cells requires signaling mediated …