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The lipid sphingosine-1-phosphate has been identified as a key exit signal for lymph nodes. In this issue of Immunity, Pham et al. (2008) show that its action can only be understood in the context of retention signals transduced by CCR7.
Sustained calcium signaling in T cells is critical for development and activation. In this issue of Immunity, Matza et al. (2007) demonstrate that the huge scaffold protein, AHNAK1, interacts with L-type calcium channels, regulates Ca 2+ influx, and defends against Leishmania major infection.
Recognition of self-antigens is required for regulatory T (Treg) cells to exert dominant tolerance. However, the mechanism by which self-reactive thymocytes are diverted into the Treg cell subset is unclear. To address this question, we looked for the immediate precursors to Treg cells within Foxp3 − CD4 + CD8 − thymocytes. By using intrathymic transfer, we found that the CD25...
T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor γ (RORγ) was shown to regulate Th17 differentiation; RORγ deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly...
C57BL/6 genetically modified mouse models are the accepted gold standard in biological studies. However, an increasing failure of translating the findings to human (patho)physiology casts doubt on using a single strain to address many questions.
B lymphocytes spread and extend membrane processes when searching for antigens and form immune synapses upon contacting cells that display antigens on their surface. Although these dynamic morphological changes facilitate B cell activation, the signaling pathways underlying these processes are not fully understood. We found that activation of the Rap GTPases was essential for these changes in B cell...
The integrin leukocyte function-associated antigen-1 (LFA-1) is important in the promotion of B cell adhesion, thereby facilitating immunological synapse (IS) formation and B cell activation. Despite this significance, the associated signaling mechanisms regulating LFA-1 activation remain elusive. Here, we show that both isoforms of the small GTPase Rac expressed by primary B cells, Rac1 and Rac2,...
T cells that produce IL-17 (T helper17 cells) are implicated in autoimmune pathogenesis. In this issue of Immunity, Yang et al. (2008) report that the closely related orphan nuclear receptors RORα and RORγt work together to regulate T helper (Th)17 cell differentiation.
In this issue, Sun et al. (2008) model the interface between a neutralizing antibody and HIV-1 glycoprotein 41 (gp41) envelope peptide in lipids. This model could help overcome a roadblock in HIV-1 vaccine development.
B cells are essential for the development and pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells are typically thought of as sources of autoantibody, but their most important pathogenetic roles may be to present autoantigens to T cells and to secrete proinflammatory cytokines. A rate-limiting step in the genesis of autoimmunity then is the activation of autoreactive...
Although rarely elicited during natural human infection, the most broadly neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus (HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral gp41. To gain insight into MPER antigenicity, immunogenicity, and viral function, we studied its structure in the lipid environment by a combination of nuclear magnetic resonance...
Appropriate development of regulatory T (Treg) cells is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg cell development. It is unclear what these missing factors are. However, signals emanating from the T cell receptor (TCR), the costimulatory receptor CD28, and the family of γc-dependent cytokine receptors are required for Treg cell development. Herein...
The mechanism by which sphingosine-1-phosphate receptor-1 (S1P 1 ) acts to promote lymphocyte egress from lymphoid organs is not defined. Here, we showed that CCR7-deficient T cells left lymph nodes more rapidly than wild-type cells did, whereas CCR7-overexpressing cells were retained for longer. After treatment with FTY720, an agonist that causes downmodulation of lymphocyte S1P 1 ...
In this issue of Immunity, the Coronin-1A gene Coro1a, which regulates cytoskeletal structure, is shown by Haraldsson et al. (2007) to be a surprising disease-susceptibility gene that contributes to the spontaneous systemic autoimmunity in the MRL mouse, a model of systemic lupus erythematosus.
Engagement of the T cell antigen receptor (TCR) during antigen presentation initiates a coordinated action of a large number of signaling proteins and ion channels. AHNAK1 is a scaffold protein, highly expressed by CD4 + T cells, and is a critical component for calcium signaling. We showed that AHNAK1-deficient mice were highly susceptible to Leishmania major infection. AHNAK1-deficient CD4...
Here, we show that a lupus-suppressing locus is caused by a nonsense mutation of the filamentous actin-inhibiting Coronin-1A gene. This mutation was associated with developmental and functional alterations in T cells including reduced migration, survival, activation, and Ca 2+ flux. T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected. By transfer of T...
Granulomas play a key role in host protection against mycobacterial pathogens, with their breakdown contributing to exacerbated disease. To better understand the initiation and maintenance of these structures, we employed both high-resolution multiplex static imaging and intravital multiphoton microscopy of Mycobacterium bovis BCG-induced liver granulomas. We found that Kupffer cells directly capture...
The cytosolic sensors Nod1 and Nod2 and Toll-like receptors (TLRs) activate defense signaling pathways in response to microbial stimuli. However, the role of Nod1 and Nod2 and their interplay with TLRs during systemic bacterial infection remains poorly understood. Here, we report that macrophages or mice made insensitive to TLRs by previous exposure to microbial ligands remained responsive to Nod1...
Throughout most of adult life, lymphocyte number remains constant because of a balance of proliferation and apoptosis. Mutation of Bim, a proapoptotic protein in the intrinsic death pathway, or Fas, a tumor necrosis factor receptor (TNFR) superfamily member of the extrinsic pathway, results in late-onset autoimmunity and increased antigen-specific CD8 + T cell responses during viral infection...
In this issue, Ishizuka et al. (2008) define human T cell-receptor recognition of an immunodominant influenza A matrix peptide bound to human leukocyte antigen HLA-A ∗ 0201 in atomic detail, raising provocative questions about β chain function.
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