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The role of cellular selection in the development of γδ T cells remains unclear. Knockout mice lacking a subset of Vγ genes, including Vγ3, contain abundant γδ T cells but are devoid of dendritic epidermal γδT cells (DETCs), which normally express an invariant Vγ3/Vδ1 γδ TCR. A rearranged Vγ2 transgene restored DETC development, but the restored DETCs selectively expressed a unique Vδ gene other than...
T cell receptor-defined subsets of γδ T cells differentially localize in cutaneous, intestinal, or reproductive epithelium. In this issue of Immunity, Xiong et al. show that murine Vγ3+ T cells undergo TCR-dependent selection in the fetal thymus that drives expression of a cutaneous homing receptor.
Regulation of tyrosine kinase-mediated cellular activation through antigen receptors is of great biological and practical significance. The evolutionarily conserved Cbl family ubiquitin ligases have emerged as key negative regulators of activated tyrosine kinase-coupled receptors, and their impaired function switches a normal immune response into autoimmunity. Cbl proteins facilitate the ubiquitinylation...
Natural interferon-producing cells (IPC) respond to viruses by secreting type I interferon (IFN) and interleukin-12 (IL-12). Toll-like receptor (TLR) 9 mediates IPC recognition of some of these viruses in vitro. However, whether TLR9-induced activation of IPC is necessary for an effective antiviral response in vivo is not clear. Here, we demonstrate that IPC and dendritic cells (DC) recognize murine...
The origin of plasmacytoid dendritic cell precursors (pDC) has been controversial. This manuscript shows that CLP and CMP both can give rise to pDCs. pDCs derived from CMP express RAG gene products and show IgHD-J rearrangement, suggesting that pDC represent a unique lineage whose gene expression program shows substantial plasticity.
Members of the Ly49 gene family of natural killer (NK) cell receptors in mice are expressed in seemingly stochastic combinations such that each NK cell expresses a handful of family members. A transcriptional switch appears to establish this interesting pattern of expression.
Murine natural killer cells selectively express members of the Ly49 family of class I MHC receptors; however, the molecular mechanism controlling probabilistic expression of Ly49 proteins has not been defined. A pair of overlapping, divergent promoters discovered in the Ly49g gene functions as a molecular switch that can produce a forward transcript containing the coding region of the gene (on position)...
The differentiation of B cells into immunoglobulin-secreting plasma cells is controlled by two transcription factors, Blimp-1 and XBP1. By gene expression profiling, we defined a set of genes whose induction during mouse plasmacytic differentiation is dependent on Blimp-1 and/or XBP1. Blimp-1-deficient B cells failed to upregulate most plasma cell-specific genes, including xbp1. Differentiating xbp1-deficient...
Cell growth during the G1 stage of the cell cycle is partly controlled by inducing c-myc expression, which in B cells is regulated by the NF-κB1 and c-Rel transcription factors. Here, we show that c-myc-dependent growth during T cell activation requires c-Rel and RelA and that blocking this growth by inhibiting protein kinase C theta (PKCθ) coincides with a failure to upregulate c-myc due to impaired...
The developmental origin of type I interferon (IFN)-producing plasmacytoid dendritic cells (PDCs) is controversial. In particular, the rearrangement of immunoglobulin heavy chain (IgH) genes in murine PDCs and the expression of pre-T cell receptor α (pTα) gene by human PDCs were proposed as evidence for their “lymphoid” origin. Here we demonstrate that PDCs capable of IFN production develop efficiently...
The Tec family tyrosine kinase, Itk, is critical for PLC-γ1 activation downstream of the TCR. Studies of Itk−/− mice have demonstrated a requirement for Itk in Th2 cytokine production and protective immunity to parasitic infections. Here we address the mechanism by which Itk regulates Th2 differentiation. We find that naive Itk−/− CD4+ T cells respond normally to cytokine skewing signals and can differentiate...
The cellular organization and relationships among precursors that initiate embryonic angiogenesis and hematopoiesis in the human have yet to be characterized. Here, we identify a subpopulation of primitive endothelial-like cells derived from human embryonic stem cells (hESCs) that express PECAM-1, Flk-1, and VE-cadherin, but not CD45 (CD45negPFV cells), and that are uniquely responsible for endothelial...
Little is known of the transcriptional events controlling the differentiation and function of dendritic cells (DC). We found that the ligand-activated transcription factor Peroxisome Proliferator Activated Receptor γ (PPARγ) is immediately upregulated after the induction of monocyte-derived DC differentiation. Activation of PPARγ changed the expression pattern of cell surface receptors and enhanced...
Cyclophilin A (CypA/Ppia) is a peptidyl-prolyl isomerase (PPIase) that binds the immunosuppressive drug cyclosporine. The resulting complex blocks T cell function by inhibiting the calcium-dependent phosphatase calcineurin. To identify the native function of CypA, long suspected of regulating signal transduction, we generated mice lacking the Ppia gene. These animals develop allergic disease, with...
Previous studies have implicated the transcription factor FoxO3a in apoptosis induction. Thus, it comes as a surprise in this issue of Immunity that lymphoproliferative disease in Foxo3a-deficient mice may be due to T cell hyperactivity instead of cell death defects. Lin and colleagues provide important new evidence that disease development is associated with NF-κB hyperactivation in T cells.
Interleukin 22 (IL-22) is mainly produced by activated Th1 cells. The data presented here indicate that neither resting nor activated immune cells express IL-22 receptor, and IL-22 did not have any effects on these cells in vitro and in vivo. In contrast, cells of the skin and the digestive and respiratory systems represent putative targets of this cytokine. The expression of IL-22 receptor in keratinocytes...
Survival of naive T cells is dependent upon IL-7, which is present in vivo in limiting amounts with the result that naive T cells must compete for IL-7-mediated survival signals. It would seem imperative during T cell homeostasis that limiting IL-7 be shared by the greatest possible number of T cells. We now describe a novel regulatory mechanism that specifically suppresses IL7Rα transcription in...
Neutrophils (PMN) have been described as critical effector cells in the host's antibacterial innate immunities. However, the classification of murine PMNs remains unclear. Here, we show that in addition to normal PMN (PMN-N), there are at least two distinct subsets of PMNs (PMN-I and PMN-II) distinguished as follows: (1) cytokine and chemokine production (PMN-I, IL-12/CCL3; PMN-II, IL-10/CCL2; PMN-N,...
The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the...
Forkhead (Fox) transcription factors play key roles in immunoregulation. Members of the Foxo subfamily have been implicated in the regulation of the cell cycle and/or apoptosis, but their specific immunological contexts remain largely undefined. We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis. Foxo3a...
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