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Lineage commitment during myelopoiesis has been linked to late-stage progenitors with multi-lineage potential. In a recent issue of Cell, Paul et al. (2015) now suggest a much earlier commitment toward distinct lineages even prior to the common myeloid progenitor state.
There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor...
Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease...
Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen-specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrated that the clonal abundance of CD4+ T cells specific for self-tumor antigen positively correlated with...
In a recent article (Helft et al., 2015), murine bone marrow (BM) cultures with granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed for macrophage (“GM-Mac”) and dendritic cell (“GM-DC”) subsets, and the GM-DC subset was compared with conventional or classical DC (cDC) subsets isolated from peripheral and lymphoid organs of mice. The article was accompanied by a preview about the...
Mucosal-associated invariant T (MAIT) cells recognize microbial non-peptidic antigens presented by non-classical MHC MR1. In this issue of Immunity, Gherardin et al. (2016) show co-crystal structures of MR1 complexed to T cell receptors (TCRs) from two classes of MAIT-type cells.
The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic...
Understanding the localization of cells is important as local environmental cues influence both phenotype and effector function. In this issue of Immunity, Pepper and colleagues find that allergen–specific tissue-resident memory T cells are maintained by IL-2 and are key drivers of allergic pathology.
Neutrophils are recruited from the blood to sites of sterile inflammation, where they are involved in wound healing but can also cause tissue damage. During sterile inflammation, necrotic cells release pro-inflammatory molecules including formylated peptides. However, the signaling pathway triggered by formylated peptides to integrin activation and leukocyte recruitment is unknown. By using spinning-disk...
Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects...
T follicular helper (Tfh) cells provide crucial support to antigen-specific B cells. In this issue of Immunity, Schultz et al. (2016) report that circulating IL-21-producing CD4+ T cells are phenotypically, transcriptionally, and functionally similar to lymphoid Tfh cells and that such HIV-specific Tfh cells were increased in RV144 trial vaccine recipients.
Exposure to inhaled allergens generates T helper 2 (Th2) CD4+ T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4+ T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific...
A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21...
Numerous studies of the anti-HIV-1 envelope glycoprotein 41 (gp41) broadly neutralizing antibody 4E10 suggest that 4E10 also interacts with membrane lipids, but the antibody regions contacting lipids and its orientation with respect to the viral membrane are unknown. Vaccine immunogens capable of re-eliciting these membrane proximal external region (MPER)-like antibodies may require a lipid component...
In response to the comments by Lutz and colleagues to our recent preview of the paper from Helft and colleagues (Helft et al., 2015), we wish to respectfully point out that granulocyte-macrophage colony-stimulating factor (GM-CSF) bone-marrow (BM) cultures have indeed allowed conceptual advances essential for our current understanding of the immunobiology of myeloid cells. However, the study by Helft...
AIF has been known to have both apoptotic and metabolic roles. Green and colleagues show that T cells, but not B cells, rely on AIF to maintain mitochondrial electron transport and that metabolic, rather than apoptotic, pathways mediate this dependence.
Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but...
The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells...
A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2+ T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative...
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