Immunology

Cohesin is a chromatin-binding factor that interacts at CTCF motifs to organize chromatin looping domains. Merkenschlager and colleagues show that cohesin regulates the inducible expression of inflammatory genes in macrophages and HSPCs and in human AML.

This Review examines the functions of a specialized population of macrophages that make direct contact with or are found within one cell thickness of the abluminal surface of blood vessels in various tissues during both steady-state conditions and pathological processes.

Although systemic infection is a hallmark of malaria disease, less is known regarding how parasitized erythrocytes interact locally with host tissues. In this Review, the authors discuss how infected erythrocytes reach different tissue environments and cause specific pathological consequences in malaria.

In classical secondary lymphoid organs (SLOs) such as lymph nodes, tonsils, and Peyer’s patches, it is well established that fibroblastic reticular cells (FRCs) play an integral role in the generation of immune responses. Nonclassical SLOs, including fat-associated lymphoid clusters (FALCs), also play important roles in systemic immunity. However, the role of FRCs in FALCs has not been previously examined. Here, using Ccl19 -driven cre to delete MYD88 in FALC-associated FRCs, Perez-Shibayama et al. report that FRCs in FALCs play both organizational and immunomodulatory roles. These studies add to the growing recognition of the importance of stromal cells in shaping immune organs and immune responses.

Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer’s patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear. Using FRC-specific gene targeting, we found that FRCs play an essential role in FALC-driven immune responses. Specifically, we report that initiation of peritoneal immunity was governed through FRC activation in a myeloid differentiation primary response 88 (MYD88)–dependent manner. FRC-specific ablation of MYD88 blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4+ T cell–dependent B-cell activation and IgG class switching. Moreover, containment of Salmonella infection was compromised in mice lacking MYD88 expression in FRCs, indicating that FRCs in FALCs function as an initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity.

In classical secondary lymphoid organs (SLOs) such as lymph nodes, tonsils, and Peyer’s patches, it is well established that fibroblastic reticular cells (FRCs) play an integral role in the generation of immune responses. Nonclassical SLOs, including fat-associated lymphoid clusters (FALCs), also play important roles in systemic immunity. However, the role of FRCs in FALCs has not been previously examined. Here, using Ccl19 -driven cre to delete MYD88 in FALC-associated FRCs, Perez-Shibayama et al. report that FRCs in FALCs play both organizational and immunomodulatory roles. These studies add to the growing recognition of the importance of stromal cells in shaping immune organs and immune responses.

Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer’s patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear. Using FRC-specific gene targeting, we found that FRCs play an essential role in FALC-driven immune responses. Specifically, we report that initiation of peritoneal immunity was governed through FRC activation in a myeloid differentiation primary response 88 (MYD88)–dependent manner. FRC-specific ablation of MYD88 blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4+ T cell–dependent B-cell activation and IgG class switching. Moreover, containment of Salmonella infection was compromised in mice lacking MYD88 expression in FRCs, indicating that FRCs in FALCs function as an initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity.

Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC has long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naïve peripheral T cells. Zfx-deficient T cells also failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell (iNKT) cell compartment was severely reduced. RNA-Seq analysis revealed that the most dysregulated genes in Zfx-deficient T cells were similar to those observed in Zfx-deficient HSC and B cells. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion, and highlight the common molecular basis of HSC and lymphocyte homeostasis.

Ugolini and colleagues show that glucocorticoid signaling induces expression of the checkpoint receptor PD-1 on NK cells to control immunopathology in a tissue-specific way.

The development of multiphoton intravital microscopy has enabled detailed studies of humoral responses within lymphoid tissues. Here, Kuka and Iannacone cover recent studies of the viral subversion of B cell responses and discuss how these findings relate to our understanding of B cell activation within secondary lymphoid organs.

Dendritic cells have the capacity to efficiently present internalized antigens on MHC I molecules. This process is termed cross-presentation and plays an important role in the generation of an immune response against viruses and tumors, after vaccinations, or in the induction of immune tolerance.The molecular mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions.Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degradation for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the transport of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field.

γδ T cells have also been shown to participate in induction of humoral immune responses by helping B cells. Whether γδ T cells directly interact with B cells or

Lymphocyte differentiation and identity are controlled by signals in the microenvironment that ultimately mediate gene expression in the nucleus. Although much focus has centered on the strategic and often unique roles transcription factors play within lymphocyte subsets, it is increasingly clear that another level of molecular regulation is crucial for regulating gene expression programs. In particular, epigenetic regulation is critical for appropriately regulated temporal and cell-type–specific gene expression during immune responses. As such, mutations in epigenetic modifiers are linked with lymphomagenesis. Furthermore, certain infections can remodel the epigenome in host cells, either through the microenvironment or by directly co-opting host epigenetic mechanisms, leading to inappropriate gene expression and/or ineffective cellular behavior. This review will focus on how histone modifications and DNA methylation, and the enzymes that regulate the epigenome, underpin lymphocyte differentiation and function in health and disease.

Dendritic cells have the capacity to efficiently present internalized antigens on MHC I molecules. This process is termed cross-presentation and plays an important role in the generation of an immune response against viruses and tumors, after vaccinations, or in the induction of immune tolerance.The molecular mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions.Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degradation for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the transport of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field.

After the first description of BCL10 in 1999 many studies have unraveled its key functions for channeling adaptive and innate immune signaling downstream of CARMA/CARD scaffold proteins. While T- and B-cell antigen receptor (TCR/BCR) signaling induces the recruitment of pre-assembled BCL10-MALT1 complexes to the lymphocyte-specific CARMA1/CARD11-BCL10-MALT1 (CBM-1) signalosome, alternative CBM complexes utilize different CARMA/CARD scaffolds in distinct innate or inflammatory pathways. With 233 amino acids encoding for an N-terminal CARD and a C-terminal Ser/Thr-rich region, BCL10 constitutes the smallest subunit in all CBM signalosomes. By forming filaments, BCL10 aggregates into higher-order clusters that mediate and amplify signaling upon stimulation leading to activation of the MALT1 protease and canonical NF-kB and JNK signaling. Moreover, BCL10 is prone to extensive post-translational regulation involving phosphorylation, ubiquitination, MALT1-catalyzed cleavage and degradation. Through these feed-back or feed-forward events BCL10 integrates positive and negative regulatory processes that govern the function as well as the dynamic assembly, disassembly and destruction of CBM complexes. Thus, BCL10 is a critical regulator for activation as well as termination of immune cell signaling, revealing that the role of BCL10 goes far beyond a mere linking factor in the CBM complexes.