The conference’s agenda reflected the field’s growing complexity and interdisciplinary reach. Among the key aims were identifying novel therapeutic targets, exchanging ideas with leading experts, and cultivating collaborative networks in immunology and infectious disease research.

Three major themes emerged as focal points of the conference:

1. Mucosal immunity and the gut-immune system interaction – Highlighting how gut microbiota shape immune responses at mucosal surfaces and in peripheral tissues like the pancreas, with implications for diseases like IBD and type 1 diabetes.
2. Neuroimmunology – Challenging the outdated notion of the brain as an immune-privileged site, this theme explored how immune signals influence brain development, behavior, and pathology through interactions in the meninges and CNS parenchyma.
3. Metabolic control of inflammation – Demonstrating how immune cell function is tightly regulated by metabolic cues, including nutrient availability, mitochondrial dynamics, and epigenetic modifications driven by cellular metabolism.

I. Mucosal immunity and the gut-immune system interaction

B cells and IL-27 in gut inflammation – Dr Shuai Wu (University of Texas Health Science Center, San Antonio)

Dr Shuai Wupresented compelling evidence that B cells are not merely antibody factories but active regulators of mucosal immunity through cytokine production. Using a DSS-induced colitis model in mice, Dr Wu discussed the role of B cell-derived IL-27 in resolving inflammation and promoting IgA production. IL-27 expression was tracked using GFP reporter mice, revealing its upregulation in gut-associated lymphoid follicles during colitis. Mice with B cell-specific IL-27 knockouts exhibited heightened sensitivity to DSS.

Interestingly, IL-27 expression was also elevated in the gut follicles of IBD patients, suggesting translational relevance. Dr Wu further showed that IL-27-expressing B cells enhanced Treg accumulation in the gut, and that IL-27 receptor signaling in RORγt+ cells was essential for this regulatory axis. These findings position IL-27 as a potential therapeutic target in IBD.

Epithelial MHC II and CD4 T cell help – Christopher Garrett Wilson (University of Alabama, Birmingham)

Wilson’s talk focused on the epithelial-immune interface during Citrobacter rodentium infection, a model for enteropathogenic E. coli. He revealed that colonocytes upregulate MHC class II to present antigens and receive help from IL-22-producing CD4 T cells. Using genetically engineered bacteria expressing a trackable gp66 antigen, Wilson showed that cytosolic localization of antigens in epithelial cells drives robust CD4 T cell responses and tissue infiltration.

Mice lacking epithelial MHC II had diminished IL-22 production and reduced STAT3 phosphorylation, impairing mucosal defense. This work highlights a novel paradigm where epithelial cells act as non-professional antigen-presenting cells to orchestrate adaptive immunity.

Cholesterol transport and T cell function – Dr Yajing Gao (UCLA)

Dr Gao introduced ASTER-A, a non-vesicular cholesterol transporter, as a T cell metabolic checkpoint. Her work demonstrated that ASTER-A is upregulated in Th17 cells and is essential for dietary lipid absorption and TCR signaling. T cell-specific ASTER-A knockout mice exhibited impaired fat absorption and altered immune responses, linking cholesterol metabolism to mucosal immunity.

Using IL-22 neutralizing antibodies, Dr Gao demonstrated that Th17 cells modulate lipid uptake in the gut, suggesting a feedback loop between immune activation and nutrient absorption. This work adds a new layer to our understanding of immunometabolism at mucosal surfaces.

Maternal IgG and Treg Induction – Jung-shan Hsu (University of Alabama, Birmingham)

Hsu explored the role of maternally derived IgG in shaping neonatal immune tolerance. Her findings showed that IgG, transported via FcRn into the colonic mucus, promotes the development of RORγt+ Foxp3+ peripheral Tregs. IgG-deficient pups exhibited reduced Treg numbers and increased susceptibility to inflammation.

FcRn knockout models confirmed the necessity of IgG transport into the gut lumen for Treg induction. These results underscore the importance of maternal antibodies in early-life immune education and tolerance.

Clostridioides difficile toxin B and immune suppression – Jeffrey Maslanka (University of Pennsylvania)

Maslanka presented data on how C. difficile toxin B suppresses adaptive immunity through its glucosyltransferase activity. Unlike toxin A, which elicits a robust IL-17A response, toxin B-specific CD4 T cells were skewed toward a Foxp3+ regulatory phenotype. This immune evasion strategy may explain the high recurrence rates of C. difficile infections and the limited efficacy of natural immunity.

KLF4 and CD4+ TRM cell survival – Dr Xu Si (University of Pittsburgh Medical Center)

Dr Wu presented research focused on the transcription factor KLF4, which is enriched in intestinal CD4+ tissue-resident memory T cells (TRMs). Using a tamoxifen-inducible knockout model, Dr Wu showed that KLF4 is essential for TRM survival during the memory phase. KLF4 also regulates lipid metabolism in TRMs, as evidenced by increased lipid droplet accumulation and altered metabolic profiles.

This work provides mechanistic insight into how TRMs persist in the gut and maintain long-term immunity following oral vaccination or infection.

II. Neuroimmunology: Immune signals shaping the brain

IL-17A and social behavior – Dr Gloria Choi (MIT)

Dr Choi’s latest findings demonstrate that IL-17A, a cytokine produced by maternal Th17 cells in response to infection, can cross the placental barrier and act directly on fetal cortical neurons. Specifically, IL-17RA is expressed in the S1DZ region of the cortex, a hub for social behavior.

In MIA offspring, LPS-induced maternal inflammation suppressed S1DZ neuronal activity in an IL-17A-dependent manner. Remarkably, direct injection of IL-17A into the S1DZ restored social behavior in these mice. Furthermore, IL-17A was shown to modulate IL-17E expression in motor neurons, suggesting a broader neuroimmune signaling axis. These findings not only elucidate a molecular mechanism linking maternal inflammation to autism-like behaviors but also open avenues for therapeutic intervention.

Cytokines in brain development – Dr Anna Victoria Molofsky (UCSF)

Dr Molofsky’s presentation expanded the neuroimmune narrative by focusing on cytokine regulation during early brain development. Her team identified IL-13, produced by ILC2s in the meninges during a critical postnatal window, as a key regulator of inhibitory synapse formation. IL-13 knockout in ILC2s led to reduced expression of VGAT and Gephyrin, markers of inhibitory synapses, and impaired social preference in adulthood. These deficits were rescued by reintroducing IL-13 or donor ILC2s.

In parallel, Dr Molofsky highlighted the role of type I interferons in shaping microglial function. IFN-responsive microglia were shown to engulf neurons during development, a process essential for tactile sensitivity regulation. Mice lacking IFNAR1 in microglia exhibited excessive synaptic pruning and altered sensory behaviors. These findings underscore the importance of tightly regulated cytokine signaling in establishing healthy neural circuits.

Autoantibodies and neuropsychiatric lupus – Stacie R. Lin (Harvard Medical School)

Lin presented a compelling case for the role of autoantibodies in neuropsychiatric lupus. Using the Sle1.Yaa lupus-prone mouse model, she showed that IgG autoantibodies deposit in the neurovasculature, particularly in astrocyte-rich regions. This deposition triggers local type I interferon responses, sustained long after peripheral inflammation subsides.

Astrocytes co-expressing IFITM3 and IgG were identified as key mediators of this response. Complement component C3 was implicated in facilitating IgG deposition and subsequent activation of myeloid cells around cerebral blood vessels. These findings suggest that persistent neuroinflammation in lupus may be driven by localized autoantibody-mediated interferon signaling, offering new targets for therapeutic intervention.

Neuro-immune interactions in the gut –Dr Daniel Mucida (Rockefeller University)

Dr Mucida’s talk bridged the gut-brain axis by exploring how helminth infections influence CNS activity via mast cell-derived serotonin. His team used the LIPSTIC technique to map interactions between intestinal epithelial cells and immune cells during infection. They found that mast cells, which expand during helminth clearance, produce serotonin that activates the nucleus of the solitary tract (NTS) in the brainstem.

This interoceptive signaling modulates feeding behavior and immune responses, highlighting a bidirectional communication pathway between the gut and brain. Blocking serotonin production in mast cells impaired NTS activation, confirming its role in helminth-induced behavioral changes.

Cryptic epitopes in neurodegeneration – Lingyang Kong (University of Pennsylvania)

Kong introduced a novel mechanism of immune recognition in neurodegenerative diseases such as ALS and inclusion body myositis (IBM). Her team identified cryptic peptides derived from TDP-43 pathology that are presented on MHC class I molecules and recognized by clonally expanded CD8+ T cells.

Using TetTCR-seqHD, they mapped T cell responses to these neoepitopes and found that their presence correlated with disease severity. This work suggests that TDP-43 aggregation not only disrupts neuronal function but also creates novel antigenic targets that may drive neuroinflammation.

Immune surveillance in the meninges – Dr Dorian McGavern (NIH/NINDS)

Dr McGavern’s presentation revealed the meninges as a dynamic immunological barrier. His team showed that the dural sinus, wrapped in smooth muscle and rich in adhesion molecules like ICAM and VCAM, hosts a diverse array of immune cells, including IgA+ B cells and neutrophils.

Blocking LFA-1/VLA-4 disrupted immune cell localization and increased susceptibility to fungal infections like Candida albicans. Additionally, the receptor RAMP2 was identified as a gatekeeper for viral entry into the sinus. These findings position the meninges as a frontline defense against CNS infections and a potential site for immunomodulation.

Stress, microbiota, and brain inflammation – Dr Christoph Thaiss (Stanford University)

Dr Thaiss explored how psychological stress exacerbates intestinal inflammation via neuroimmune pathways. His team found that stress increases monocyte accumulation in the gut by disrupting the “waterfall” of myeloid differentiation. This effect was mediated by adrenergic signaling and could be reversed by anti-TNF therapy or glucocorticoid receptor blockade.

In a model of Hirschsprung disease, mice lacking enteric neurons in the distal colon exhibited high mortality and inflammation. A protective diet improved mitochondrial health and barrier function, while antibiotic treatment and molybdenum cofactor supplementation further enhanced survival. These findings highlight the intricate interplay between the nervous system, microbiota, and immune responses in stress-related disease.

III. Metabolic control of inflammation and immune function

Branched-chain amino acids and inflammasome activation – Dr Mikel Haggadone (University of Pennsylvania)

Dr Haggadone’s work illuminated how nutrient availability, particularly branched-chain amino acids (BCAAs), regulates inflammasome activation. He demonstrated that BCAA starvation licenses the assembly of the NLRP3 inflammasome and promotes IL-1β release. Using confocal imaging, he showed that NLRP3 and PYCARD form perinuclear specks upon stimulation with LPS and nigericin, a hallmark of inflammasome activation.

This nutrient-sensing mechanism suggests that metabolic stress can act as a danger signal, priming innate immune cells for inflammatory responses. These findings have implications for diseases characterized by metabolic dysregulation, such as obesity and type 2 diabetes.

VISTA and ILC2 metabolism – Dr Mohammed Kazemi (USC Keck School of Medicine)

Dr Kazemi explored the role of the immune checkpoint molecule  VISTAin regulating type 2 innate lymphoid cells (ILC2s) in the lung. He found that VISTA expression is induced by IL-33 and modulates ILC2 metabolism via the Akt-FOXO1 and NF-κB pathways. VISTA-deficient ILC2s exhibited heightened oxidative phosphorylation and fatty acid oxidation, leading to exaggerated type 2 inflammation in asthma models.

Treatment with a VISTA agonist (MH5A) reversed this phenotype, reducing eosinophilic infiltration and cytokine production. These findings suggest that targeting VISTA could offer a novel approach to modulating ILC2-driven diseases such as asthma and allergic inflammation.

Ketogenic diet and klebsiella clearance – Dr Tania Wong (Rutgers New Jersey Medical School)

Dr Wong presented a striking example of diet-mediated immunometabolic regulation. Her team showed that a ketogenic diet enhances clearance of  Klebsiella pneumoniae  from the lungs by reprogramming alveolar macrophages and neutrophils. Using spatial metabolomics (DESI-MSI), they demonstrated increased ketone accumulation in lung tissue, which correlated with enhanced immune cell effector functions.

Met-flow analysis revealed that macrophages under ketogenic conditions upregulated PD-L1 and exhibited increased oxidative metabolism. Neutrophils also showed enhanced antimicrobial activity. These findings suggest that dietary interventions could be leveraged to boost host defense against respiratory pathogens.

Fatty acid oxidation in alveolar macrophages – Dr Ananya Ranaraja (University of Arkansas)

Dr Ranaraja focused on the role of fatty acid oxidation (FAO) in maintaining alveolar macrophage homeostasis. Using a Cpt1a conditional knockout model, she showed that FAO-deficient macrophages were reduced in number and exhibited altered amino acid transporter expression. These cells also displayed increased mTORC1 activity and protein translation, as measured by puromycin incorporation.

This metabolic imbalance impaired macrophage function and increased susceptibility to infection. Her findings underscore the importance of FAO in sustaining lung immune surveillance and suggest that metabolic reprogramming could be a therapeutic strategy in pulmonary diseases.

Itaconate and redox regulation – Dr Tomas Paulenda (Washington University in St. Louis)

Dr Paulenda presented new insights into how the metabolite itaconate modulates immune responses by targeting redox enzymes. His team identified peroxiredoxin 5 (Prdx5) as a direct target of itaconate, which modifies cysteine residues and inhibits its antioxidant activity. This inhibition boosts type I interferon production in macrophages stimulated with poly(I:C) or DMXAA.

These findings link metabolic rewiring to redox signaling and antiviral immunity. The therapeutic potential of modulating itaconate pathways is particularly relevant in the context of viral infections and cancer immunotherapy.

Histone acetylation and T cell exhaustion – Dr Shixin Ma (Salk Institute)

Dr Ma’s talk bridged metabolism and epigenetics by showing how nutrient-derived acetyl-CoA sources influence histone acetylation and CD8+ T cell fate. She demonstrated that glucose-derived acetyl-CoA (via ACLY) and acetate-derived acetyl-CoA (via ACSS2) differentially regulate H3K27ac marks in progenitor versus exhausted T cells.

ACSS2-deficient T cells exhibited impaired anti-tumor responses and larger tumors, while ACLY-deficient cells had enhanced tumor control. These findings suggest that manipulating acetyl-CoA metabolism could reprogram T cell exhaustion and improve immunotherapy outcomes.

GCN2-mTOR crosstalk in efferocytosis – Dr Sara Lamorte (University Health Network)

Dr Lamorte explored how amino acid sensing via GCN2 intersects with mTOR signaling during efferocytosis. She showed that GCN2 is activated under amino acid deprivation and interacts with mTOR to regulate macrophage reprogramming. In the absence of GCN2, mTORC1 remains hyperactive, impairing the resolution of inflammation.

This work highlights the delicate balance between nutrient sensing and immune resolution, with implications for chronic inflammatory diseases and tissue repair.

Treg metabolism in non-lymphoid tissues – Pamela P. Diaz-Saldana (Emory University)

Diaz-Saldana investigated how regulatory T cells (Tregs) adapt metabolically to hypoxic environments like the skin. Using Scenith analysis, she showed that skin Tregs rely on oxidative phosphorylation but retain high glycolytic capacity. Disruption of glycolysis via LDHA or GLUT1 knockout led to exacerbated skin inflammation in hypersensitivity models.

These findings emphasize the metabolic flexibility of Tregs and the importance of local environmental cues in shaping their function.

Protein aggregation and T cell exhaustion – Dr Yi Wang (Pelotonia Institute for Immuno-Oncology)

Dr Wang presented a novel mechanism of CD8+ T cell exhaustion involving heightened protein synthesis and aggregation. Using proteomic analysis and OP-puromycin labeling, they showed that chronically stimulated T cells accumulate misfolded proteins, overwhelming the quality control machinery.

This proteotoxic stress contributes to functional exhaustion and may represent a new target for rejuvenating T cell responses in cancer.

3HKA and non-canonical AhR signaling – Dr Cristina Clement (Weill Cornell Medicine)

Clement introduced 3-hydroxy-L-kynurenamine (3HKA), a tryptophan-derived biogenic amine, as a novel anti-inflammatory mediator. 3HKA binds to the aryl hydrocarbon receptor (AhR) in the cytosol but does not activate its genomic targets. Instead, it inhibits IFN-γ receptor signaling via a PKA-dependent mechanism.

In vivo, 3HKA promoted Treg recruitment and suppressed inflammation in models of psoriasis and skin hypersensitivity. Elevated 3HKA levels were also associated with survival in COVID-19 patients, suggesting broad immunoregulatory potential.

The AAI 2025 conference showcased the remarkable complexity and integration of immune responses across tissues and systems. From the gut to the brain to the metabolic machinery of immune cells, the talks highlighted how immune function is shaped by its environment—and how understanding these interactions can unlock new therapeutic strategies.