ImmunoHorizons最新文献

Malaria-induced bacteremia has been shown to result from intestinal mast cell (MC) activation. The appearance of MCs in the ileum and increased intestinal permeability to enteric bacteria are preceded by an early Th2-biased host immune response to infection, characterized by the appearance of IL-4, IL-10, mast cell protease (Mcpt)1 and Mcpt4, and increased circulating basophils and eosinophils. Given the functional similarities of basophils and MCs in the context of allergic inflammation and the capacity of basophils to produce large amounts of IL-4, we sought to define the role of basophils in increased intestinal permeability, in MC influx, and in the development of bacteremia in the context of malaria. Upon infection with nonlethal Plasmodium yoelii yoelii 17XNL, Basoph8 × ROSA-DTα mice or baso (-) mice that lack basophils exhibited increased intestinal permeability and increased ileal MC numbers, without any increase in bacterial 16S ribosomal DNA copy numbers in the blood, relative to baso (+) mice. Analysis of cytokines, chemokines, and MC-associated factors in the ileum revealed significantly increased TNF-α and IL-13 at day 6 postinfection in baso (-) mice compared with baso (+) mice. Moreover, network analysis of significantly correlated host immune factors revealed profound differences between baso (-) and baso (+) mice following infection in both systemic and ileal responses to parasites and translocated bacteria. Finally, basophil depletion was associated with significantly increased gametocytemia and parasite transmission to Anopheles mosquitoes, suggesting that basophils play a previously undescribed role in controlling gametocytemia and, in turn, mammalian host-to-mosquito parasite transmission.

Type 2 immunity plays an important role in host defense against helminths and toxins while driving allergic diseases. Despite progress in understanding the biology of type 2 immunity, the fundamental mechanisms regulating the type 2 immune module remain unclear. In contrast with structural recognition used by pattern recognition receptors, type 2 immunogens are sensed through their functional properties. Functional recognition theory has arisen as the paradigm for the initiation of type 2 immunity. However, the vast array of structurally unrelated type 2 immunogens makes it challenging to advance our understanding of type 2 immunity. In this article, we review functional recognition theory and organize type 2 immunogens into distinct classes based on how they fit into the concept of functional recognition. Lastly, we discuss areas of uncertainty in functional recognition theory with the goal of providing a framework to further define the logic of type 2 immunity in host protection and immunopathology.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function CXCR4 mutations that promote severe panleukopenia caused by bone marrow retention of mature leukocytes. Consequently, WHIM patients develop recurrent bacterial infections; however, sepsis is uncommon. To study this clinical dichotomy, we challenged WHIM model mice with LPS. The LD₅₀ was similar in WHIM and wild-type (WT) mice, and LPS induced acute lymphopenia in WT mice that was Cxcr4 independent. In contrast, in WHIM mice, LPS did not affect circulating T cell levels, but the B cell levels anomalously increased because of selective, cell-intrinsic, and Cxcr4 WHIM allele-dependent emergence of Cxcr4^high late pre-B cells, a pattern that was phenocopied by Escherichia coli infection. In both WT and WHIM mice, the CXCR4 antagonist AMD3100 rapidly increased circulating lymphocyte levels that then rapidly contracted after subsequent LPS treatment. Thus, LPS-induced lymphopenia is CXCR4 independent, and a WHIM mutation does not increase clinical LPS sensitivity. Anomalous WT Cxcr4-independent, but Cxcr4 WHIM-dependent, promobilizing effects of LPS on late pre-B cell mobilization reveal a distinct signaling pathway for the variant receptor.

Apoptotic cell clearance by professional and nonprofessional phagocytes in the process of efferocytosis is critical to preserve tissue homeostasis. Uptake of apoptotic cells by dendritic cells generates regulatory T cells and induces immunologic tolerance against self-antigens. In contrast, ingestion of infected apoptotic cells promotes activation of TLR4/MyD88-dependent bone marrow-derived dendritic cells (BMDCs) and triggers Th17 cell differentiation. In this study, we evaluated the impact of Streptococcus pneumoniae-infected apoptotic cell efferocytosis by BMDCs derived from C57BL/6 mice on differentiation and expansion of CD4⁺ T cell subsets, as well as the role of TLR2/4 and receptor-interacting protein 2 (RIP2) receptors in recognizing intracellular pathogens during efferocytosis. We demonstrated that BMDC-mediated efferocytosis of S. pneumoniae-infected apoptotic cells induced Th1 cell differentiation and expansion. Although TLR2/4 and RIP2 deficiency in BMDCs did not affect Th1 cell differentiation during efferocytosis, the absence of RIP2 decreased IFN-γ production by CD4 T cells during the expansion phase. These findings suggest that RIP2-mediated IL-1β production during efferocytosis of S. pneumoniae-infected apoptotic cells partially supports a Th1-mediated IFN-γ production microenvironment.

Foxp3⁺ cells and CTLA-4 have been ascribed major roles in downregulating immune responses. To address the relationship between CTLA-4 expression and Foxp3⁺ cells, we generated littermate CTLA-4-sufficient (Ctla4 ^+/+), CTLA-4-haploinsufficient (Ctla4 ^+/-), and CTLA-4-deficient (Ctla4 ^-/-) Foxp3-gfp knock-in C57BL/6 mice, permitting us to characterize the phenotype of Foxp3⁺ cells and to test their ex vivo T regulatory (Treg) suppressor activity. CD3⁺, CD4⁺, and CD8⁺ cells, but not CD19⁺ cells, were markedly expanded in Ctla4 ^-/- mice compared with Ctla4 ^+/+ or Ctla4 ^+/- mice. In Ctla4 ^-/- mice, the relative expansion of the Foxp3⁺ population was greater than that of the CD3⁺, CD4⁺, or CD8⁺ populations because of increased survival of Foxp3⁺ cells. Foxp3⁺ Treg cells from Ctla4 ^-/- mice and Foxp3⁺ Treg cells from Ctla4 ^+/+ mice exerted identical ex vivo suppressor function. This may be related to differential expression of GITR, CD73, and CD39 on Foxp3⁺ Treg cells from Ctla4 ^-/- mice versus that on corresponding cells from littermate Ctla4 ^+/+ or Ctla4 ^+/- mice, with GITR and CD39 being upregulated and CD73 being downregulated on Foxp3⁺ Treg cells from Ctla4 ^-/- mice. Moreover, CTLA-4 expression in Ctla4 ^+/+, Ctla4 ^+/-, and Ctla4 ^-/- mice correlated with their percentages of Foxp3⁺ cells, suggesting an important role for CTLA-4 expression in Treg cell homeostasis. This may have vital ramifications for the treatment of patients for whom augmentation of suppressor function would be beneficial (e.g., patients with autoimmune diseases) and for whom diminution of suppressor function would be beneficial (e.g., patients with cancer).

Sepsis, an amplified immune response to systemic infection that leads to life-threatening organ dysfunction, affects >125,000 people/day worldwide with 20% mortality. Modest therapeutic progress for sepsis has been made, in part because of the lack of therapeutic translatability between mouse-based experimental models and humans. One potential reason for this difference stems from the extensive use of immunologically naive specific pathogen-free mice in preclinical research. To address this issue, we used sequential infections with well-defined BSL-2 pathogens to establish a novel immune-experienced mouse model (specific pathogen experienced [SPexp]) to determine the extent to which immunological experience and/or inflammation influences the host capacity to respond to subsequent infections, including sepsis. Consistent with their immunological experience, SPexp inbred or outbred mice had significant changes in the composition and activation status of multiple leukocyte populations known to influence the severity of cecal ligation and puncture-induced sepsis. Importantly, by varying the timing of sepsis induction, we found the level of basal inflammation controls sepsis-induced morbidity and mortality in SPexp mice. In addition, although a beneficial role of NK cells in sepsis was recently demonstrated in specific pathogen-free mice, NK cell depletion before cecal ligation and puncture induction in SPexp mice lead to diminished mortality, suggesting NK cells may have beneficial or detrimental roles in the response to septic insult dependent on host immune status. Thus, data highlight the importance of utilizing immune-experienced models for preclinical studies to interrogate the cellular/molecular mechanism(s) that could be therapeutically exploited during severe and dysregulated infection-induced inflammatory responses, such as sepsis.

Murine peripheral lymph node TCR γδ T cells have been divided into type 1 and type 17 functional categories based on phenotypic and functional markers. Localized in the gut epithelial barrier, intestinal intraepithelial lymphocytes (iIEL) γδ T cells constitute a peculiar subset of T lymphocytes involved in intestinal homeostasis. However, whether iIEL γδ T cells obey the type 1/type 17 dichotomy is unclear. Using both global transcriptional signatures and expression of cell surface markers, we reveal that murine iIEL γδ T cells compose a distinct population, expressing ∼1000 specific genes, in particular genes that are responsible for cytotoxicity and regulatory functions. The expression of the transcription factor Helios is a feature of iIEL γδ T cells, distinguishing them from the other TCR γδ T subsets, including those present in the epithelia of other tissues. The marked expression of Helios is also shared by the other iIELs, TCRαβCD8αα lymphocytes present within the intestinal epithelium. Finally, we show that Helios expression depends in part on TGF-β signaling but not on the microbiota. Thus, our study proposes iIEL γδ T cells as a distinct subset and identifies novel markers to differentiate them from their peripheral counterparts.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the CNS that resembles multiple sclerosis and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. We have previously shown that oral adrenocorticotropic hormone (ACTH) decreased IL-17 in the gut lamina propria and the spleen and increased CD4⁺ Foxp3⁺ T regulatory cells and IL-10 in the spleen during EAE in the C57BL/6 mouse. However, we did not investigate the specific cellular alterations of proinflammatory and anti-inflammatory factors in the CNS. The aim was to determine if oral ACTH would have a similar clinical effect on inflammatory cytokines in the gut and define specific cellular effects in the CNS in an alternative strain of mice. SJL/J mice were immunized with proteolipid protein peptide 138-151 and gavaged with scrambled ACTH (scrambled α-melanocyte-stimulating hormone) or ACTH 1-39 during ongoing disease. Ingested (oral) ACTH attenuated ongoing clinical EAE disease, decreased IL-6 production, and increased T regulatory cells in the lamina propria and decreased CD4⁺ and γδ IL-17 production in the CNS. Ingested ACTH attenuated EAE clinical disease by decreasing IL-6 in the gut-associated lymphoid tissue and decreasing IL-17 in the CNS.

Teaching and learning complex molecular cascades can often be challenging. In immunology, students struggle to visualize immunological processes, such as activation of the complement system, which involves three separate cascades leading to multiple effector functions. Offering learning activities that use tangible modeling can help students learn conceptually difficult content by fostering a visual understanding of concepts, as well as instill confidence and interest in the material. In this article, we describe a learning activity using LEGO bricks that demonstrates the activation of the classical, lectin, and alternative complement pathways and formation of the membrane attack complex. In both an introductory and advanced immunology course, we investigated the effect of the activity on student learning and subject confidence. Performance on examination questions about complement demonstrated that the LEGO activity improved learning in a naive student population (students in introductory immunology), but not in a previously informed student population (students in advanced immunology). In addition, self-reported confidence in the content was significantly higher in students who completed the LEGO activity in the advanced course, but not the introductory course, compared with those who did not do the activity. Students in both courses who did the activity had a positive perception of the activity, with a majority of students reporting that they enjoyed the activity and had more interest in the complement system.

Besides the prototypic innate and adaptive pathways, immune responses by innate-like lymphocytes have gained significant attention due to their unique roles. Among innate-like lymphocytes, unconventional T cells such as NKT cells and mucosal-associated invariant T (MAIT) cells recognize small nonpeptide molecules of specific chemical classes. Endogenous or microbial ligands are loaded to MHC class I-like molecule CD1d or MR1, and inducing immediate effector T cell and ligand structure is one of the key determinants of NKT/MAIT cell functions. Unconventional T cells are in close, constant contact with symbiotic microbes at the mucosal layer, and CD1d/MR1 can accommodate diverse metabolites produced by gut microbiota. There is a strong interest to identify novel immunoactive molecules of endobiotic (symbiont-produced) origin as new NKT/MAIT cell ligands, as well as new cognate Ags for previously uncharacterized unconventional T cell subsets. Further studies will open an possibility to explore basic biology as well as therapeutic potential.