The structurally and functionally related interleukin‐4 (IL‐4) and IL‐13 cytokines play pivotal roles in shaping immune activity. The IL‐4/IL‐13 axis is best known for its critical role in T helper 2 (Th2) cell‐mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL‐4 and IL‐13 stimulate a wide range of innate and adaptive immune cells, as well as non‐hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL‐4/IL‐13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL‐4/IL‐13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL‐4 and IL‐13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL‐4/IL‐13 biology and enabling researchers to exploit these insights to develop effective interventions.
Secreted IgM (sIgM) is a multifunctional evolutionary conserved antibody that is critical for the maintenance of tissue homeostasis as well as the development of fully protective humoral responses to pathogens. Constitutive secretion of self- and polyreactive natural IgM, produced mainly by B-1 cells, provides a circulating antibody that engages with autoantigens as well as invading pathogens, removing apoptotic and other cell debris and initiating strong immune responses. Pathogen-induced IgM production by B-1 and conventional B-2 cells strengthens this early, passive layer of IgM-mediated immune defense and regulates subsequent IgG production. The varied effects of secreted IgM on immune homeostasis and immune defense are facilitated through its binding to numerous different cell types via different receptors. Recent studies identified a novel function for pentameric IgM, namely as a transporter for the effector protein ″apoptosis-inhibitor of macrophages″ (AIM/CD5L). This review aims to provide a summary of the known functions and effects of sIgM on immune homeostasis and immune defense, and its interaction with its various receptors, and to highlight the many critical immune regulatory functions of this ancient and fascinating immunoglobulin.
more » « less- NSF-PAR ID:
- 10394153
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Journal of Leukocyte Biology
- Volume:
- 106
- Issue:
- 5
- ISSN:
- 0741-5400
- Page Range / eLocation ID:
- p. 1021-1034
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Summary -
null (Ed.)At the host–pathogen interface, the protein composition of the plasma membrane (PM) has important implications for how a plant cell perceives and responds to invading microbial pathogens. A plant's ability to modulate its PM composition is critical for regulating the strength, duration, and integration of immune responses. One mechanism by which plant cells reprogram their cell surface is vesicular trafficking, including secretion and endocytosis. These trafficking processes add or remove cargo proteins (such as pattern-recognition receptors, transporters, and other proteins with immune functions) to or from the PM via small, membrane-bound vesicles. Clathrin-coated vesicles (CCVs) that form at the PM and trans-Golgi network/early endosomes have emerged as the prominent vesicle type in the regulation of plant immune responses. In this review, we discuss the roles of the CCV core, adaptors, and accessory components in plant defense signaling and immunity against various microbial pathogens.more » « less
-
more » « less
Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.
-
more » « less
Abstract Diverse T and B cell repertoires play an important role in mounting effective immune responses against a wide range of pathogens and malignant cells. The number of unique T and B cell clones is characterized by T and B cell receptors (TCRs and BCRs), respectively. Although receptor sequences are generated probabilistically by recombination processes, clinical studies found a high degree of sharing of TCRs and BCRs among different individuals. In this work, we use a general probabilistic model for T/B cell receptor clone abundances to define “publicness” or “privateness” and information-theoretic measures for comparing the frequency of sampled sequences observed across different individuals. We derive mathematical formulae to quantify the mean
and the variances of clone richness and overlap. Our results can be used to evaluate the effect of different sampling protocols on abundances of clones within an individual as well as the commonality of clones across individuals. Using synthetic and empirical TCR amino acid sequence data, we perform simulations to study expected clonal commonalities across multiple individuals. Based on our formulae, we compare these simulated results with the analytically predicted mean and variances of the repertoire overlap. Complementing the results on simulated repertoires, we derive explicit expressions for the richness and its uncertainty for specific, single-parameter truncated power-law probability distributions. Finally, the information loss associated with grouping together certain receptor sequences, as is done in spectratyping, is also evaluated. Our approach can be, in principle, applied under more general and mechanistically realistic clone generation models. -
more » « less
Abstract Herein, this work reports the first synthetic vaccine adjuvants that attenuate potency in response to small, 1–2 °C changes in temperature about their lower critical solution temperature (LCST). Adjuvant additives significantly increase vaccine efficacy. However, adjuvants also cause inflammatory side effects, such as pyrexia, which currently limits their use. To address this, a thermophobic vaccine adjuvant engineered to attenuate potency at temperatures correlating to pyrexia is created. Thermophobic adjuvants are synthesized by combining a rationally designed trehalose glycolipid vaccine adjuvant with thermoresponsive poly‐
N ‐isoporpylacrylamide (NIPAM) via reversible addition fragmentation chain transfer (RAFT) polymerization. The resulting thermophobic adjuvants exhibit LCSTs near 37 °C, and self‐assembled into nanoparticles with temperature‐dependent sizes (90–270 nm). Thermophobic adjuvants activate HEK‐mMINCLE and other innate immune cell lines as well as primary mouse bone marrow derived dendritic cells (BMDCs) and bone marrow derived macrophages (BMDMs). Inflammatory cytokine production is attenuated under conditions mimicking pyrexia (above the LCST) relative to homeostasis (37 °C) or below the LCST. This thermophobic behavior correlated with decreased adjuvantR gis observed by DLS, as well as glycolipid‐NIPAM shielding interactions are observed by NOESY‐NMR. In vivo, thermophobic adjuvants enhance efficacy of a whole inactivated influenza A/California/04/2009 virus vaccine, by increasing neutralizing antibody titers and CD4+/44+/62L+lung and lymph node central memory T cells, as well as providing better protection from morbidity after viral challenge relative to unadjuvanted control vaccine. Together, these results demonstrate the first adjuvants with potency regulated by temperature. This work envisions that with further investigation, this approach can enhance vaccine efficacy while maintaining safety.
