Current Opinion in Immunology

mRNA vaccines have played a critical role in controlling the SARS-CoV-2 pandemic, and are being actively studied for use in other diseases. There is a growing interest in applying mRNA vaccines at mucosal surfaces as it enables access to a unique immune reservoir in a less-invasive manner. However, mucosal surfaces present several barriers to mRNA uptake, including degrading enzymes, mucus, and clearance mechanisms. In this mini-review, we discuss our understanding of the immune response to mucosal mRNA vaccines as it compares to systemic mRNA vaccines...

The eradication of polio during the latter half of the 20th century can be considered one of the greatest medical triumphs in history. This achievement can be attributed to the development of vaccines that received the public's almost unwavering acceptance of them, especially by parents who had been waiting/hoping for a medical breakthrough that would ensure that their children would not succumb to the devastating effects of infantile paralysis. Sixty years later, the worldwide population was now confronted with an equally devastating disease - Covid-19 - which by the 2020-2021 time period had reached pandemic levels not seen since the flu outbreak of 1918...

Conventional dendritic cells (cDCs) are potent antigen-presenting cells that consist of developmentally, phenotypically, and functionally distinct subsets. Following immunization, each subset of cDCs acquires the antigen and presents it to CD4T (CD4+ T (cells)) cells with distinct spatiotemporal kinetics in the secondary lymphoid organs, often causing multiple waves of antigen presentation to CD4T cells. Here, we review the current understanding of the kinetics of antigen presentation by each cDC subset and its functional consequences in priming naive CD4T cells, and discuss its implications in the differentiation of CD4T cells...

At mucosal barriers, the T helper 17 (TH 17) cell population plays a fundamental role in controlling tissue homeostasis. The adaptability of this population to a more pro-inflammatory or anti-inflammatory function - that is, their functional plasticity and consequently heterogeneity - primarily depends on the environment. We would like to term this process environmental immune adaptation. Interfering with TH 17 cell adaptation leads to pathological consequences, including development of immune-mediated inflammatory diseases or even cancer...

The detrimental impact of fungal infections to human health has steadily increased over the past decades. In October of 2022, the World Health Organization published the first ever fungal-pathogen priority list highlighting increased awareness of this problem, and the need for more research in this area. There were four distinct fungal pathogens identified as critical priority groups with Aspergillus fumigatus (Af) being the only mold. Af is a common environmental fungus responsible for over 90% of invasive aspergillosis cases worldwide...

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea in children in developing countries and in travelers. WHO has affirmed ETEC as a priority vaccine target, but there is no licensed ETEC vaccine available yet. We here describe recent, promising developments of different live, inactivated, and subunit ETEC candidate vaccines expressing or containing nontoxic enterotoxin and/or colonization factor antigens with a focus on oral vaccines. Many of the ETEC candidate vaccines have been tested in clinical trials for safety and immunogenicity and some of them also for protective efficacy in field trials or in challenge studies...

Increasing global concerns of pandemic respiratory viruses highlight the importance of developing optimal vaccination strategies that encompass vaccine platform, delivery route, and regimens. The decades-long effort to develop vaccines to combat respiratory infections such as influenza, respiratory syncytial virus, and tuberculosis has met with challenges, including the inability of systemically administered vaccines to induce respiratory mucosal (RM) immunity. In this regard, ample preclinical and available clinical studies have demonstrated the superiority of RM vaccination to induce RM immunity over parenteral route of vaccination...

Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages rewire their energy metabolism to execute their immune programs. Intensive research in the field of immunometabolism highlights cell-intrinsic immunometabolites such as succinate and itaconate as immunomodulatory signals. A role for cell-extrinsic stimuli now emerges with evidence for signals that shape macrophages' metabolism in a tissue-specific manner...

In addition to housing the major energy-producing pathways in cells, mitochondria are active players in innate immune responses. One critical way mitochondria fulfill this role is by releasing damage-associated molecular patterns (mtDAMPs) that are recognized by innate sensors to activate pathways including, but not limited to, cytokine expression, selective autophagy, and cell death. Mitochondrial reactive oxygen species (mtROS) is a multifunctional mtDAMP linked to pro- and antimicrobial immune outcomes...

Over recent years, the use of immune checkpoint inhibitors (ICI) has progressed to first and second-line treatments in several cancer types, transforming patient outcomes. While these treatments target T cell checkpoints, such as PD-1, LAG3 and CTLA-4, their efficacy can be compromised through adaptive resistance whereby tumors acquire mutations in genes regulating neoantigen presentation by MHC-I [93]. ICI-responsive tumor types such as advanced metastatic melanoma typically have a high mutational burden and immune infiltration; however, most patients still do not benefit from ICI monotherapy for a number of reasons [94]...

Granulocytes are innate immune effector cells with essential functions in host resistance to bacterial infections. I will discuss emerging evidence that during Mycobacterium tuberculosis infection, counter-intuitively, eosinophils are host-protective while neutrophils are host detrimental. Additionally, I will propose a 'tipping-point' model in which neutrophils are an integral part of a feedforward loop driving tuberculosis disease exacerbation.

Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche...

Major histocompatibility complex class I (MHC class I) molecules facilitate subcellular immune surveillance by presenting peptides on the cell surface. MHC class I assembly with peptides generally happens in the endoplasmic reticulum (ER). Peptides are processed in the cytosol, transported into the ER, and assembled with MHC class I heavy and light chains. However, as many pathogens reside within multiple subcellular organelles, peptide sampling across non-cytosolic compartments is also important...

ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease...

Effective adaptive immunity is rendered possible by highly organized tissue architecture and coordinated cellular crosstalk. While detailed spatiotemporal analyses of antigen presentation and adaptive immune activation in secondary lymphoid tissues have been a major focus of study, it is clear that antigen presentation in other tissues also plays a critical role in shaping the immune response. In this article, we concentrate on two opposing aspects of adaptive immunity: tolerance and antitumor immunity, to illustrate how a complex set of antigen presentation mechanisms contributes to maintaining a delicate balance between robust immunity and avoidance of autoimmune pathology...

Host innate immune sensors are vital for the initial detection of pathogen infection. Such sensors thus need to constantly adapt in escalating evolutionary arms races with pathogens. Recently, two inflammasome-forming proteins, CARD8 and NLRP1, have emerged as innate immune sensors for the enzymatic activity of virus-encoded proteases. When cleaved within a rapidly evolving 'tripwire' region, CARD8 and NLRP1 assemble into inflammasomes that initiate pyroptotic cell death and pro-inflammatory cytokine release as a form of effector-triggered immunity...

Since the discovery of Transporter associated with antigen processing-binding protein-related (TAPBPR) over two decades ago, extensive studies have explored its function in the context of the major histocompatibility complex class-I (MHC-I) antigen processing and presentation pathway. As a chaperone and peptide editor, TAPBPR was recently revealed to have overlapping structural features when resolved with peptide-receptive MHC-I molecules compared with the two newly solved tapasin:MHC-I structures. Despite this, the two chaperones seem to have a unique criteria for loading high-affinity peptides on MHC-I molecules...

Z-form nucleic acid-binding protein 1 (ZBP1) detects viral Z-form RNAs (Z-RNAs), activates receptor-interacting protein kinase 3, and triggers cell death during both RNA and DNA virus infections. Such cell death promotes virus clearance by eliminating infected cells and galvanizing antiviral immunity, and is thus often targeted for evasion by virus-encoded suppressors. Recent evidence demonstrates that ZBP1 can also be activated by cellular Z-RNAs transcribed from endogenous retroelements within mammalian genomes...

Metabolite-based T-cell immunity is emerging as a major player in antimicrobial immunity, autoimmunity, and cancer. Here, small-molecule metabolites were identified to be captured and presented by the major histocompatibility complex class-I-related molecule (MR1) to T cells, namely mucosal-associated invariant T cells (MAIT) and diverse MR1-restricted T cells. Both MR1 and MAIT are evolutionarily conserved in many mammals, suggesting important roles in host immunity. Rational chemical modifications of these naturally occurring metabolites, termed altered metabolite ligands (AMLs), have advanced our understanding of the molecular correlates of MAIT T cell receptor (TCR)-MR1 recognition...

Type 1 classical dendritic cells (cDC1s) have emerged as the major antigen-presenting cell performing cross-presentation (XP) in vivo, but the antigen-processing pathway in this cell remains obscure. Two competing models for in vivo XP of cell-associated antigens by cDC1 include a vacuolar pathway and cytosolic pathway. A vacuolar pathway relies on directing antigens captured in vesicles toward a class I major histocompatibility complex loading compartment independently of cytosolic entry. Alternate proposals invoke phagosomal rupture, either constitutive or triggered by spleen tyrosine kinase (SYK) signaling in response to C-type lectin domain family 9 member A (CLEC9A) engagement, that releases antigens into the cytosol for proteasomal degradation...