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1.
Cell ; 187(9): 2052-2078, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38670065

RESUMEN

Adaptive immunity provides protection against infectious and malignant diseases. These effects are mediated by lymphocytes that sense and respond with targeted precision to perturbations induced by pathogens and tissue damage. Here, we review key principles underlying adaptive immunity orchestrated by distinct T cell and B cell populations and their extensions to disease therapies. We discuss the intracellular and intercellular processes shaping antigen specificity and recognition in immune activation and lymphocyte functions in mediating effector and memory responses. We also describe how lymphocytes balance protective immunity against autoimmunity and immunopathology, including during immune tolerance, response to chronic antigen stimulation, and adaptation to non-lymphoid tissues in coordinating tissue immunity and homeostasis. Finally, we discuss extracellular signals and cell-intrinsic programs underpinning adaptive immunity and conclude by summarizing key advances in vaccination and engineering adaptive immune responses for therapeutic interventions. A deeper understanding of these principles holds promise for uncovering new means to improve human health.


Asunto(s)
Inmunidad Adaptativa , Humanos , Animales , Linfocitos B/inmunología , Linfocitos T/inmunología , Autoinmunidad/inmunología
2.
Immunity ; 57(4): 843-858.e5, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38513666

RESUMEN

Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. Here, we showed that IL-4 cytokine signaling in GC B cells directly downregulated the transcription factor BCL6 via negative autoregulation to release cells from the GC program and to promote MBC formation. This selection event required additional survival cues and could therefore result in either GC exit or death. We demonstrate that both increasing IL-4 bioavailability or limiting IL-4 signaling disrupted MBC selection stringency. In this way, IL-4 control of BCL6 expression serves as a tunable switch within the GC to tightly regulate MBC selection and affinity maturation.


Asunto(s)
Interleucina-4 , Factores de Transcripción , Linfocitos B , Centro Germinal , Interleucina-4/metabolismo , Células B de Memoria , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factores de Transcripción/metabolismo
3.
Immunol Cell Biol ; 102(7): 532-534, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38715314

RESUMEN

Long-lived plasma cells are important for preventing infection by maintaining baseline antibody titers. However, the cues leading to plasma cell differentiation remain unclear. In this article, we discuss recent work assessing the role of affinity on plasma cell differentiation.


Asunto(s)
Diferenciación Celular , Células Plasmáticas , Animales , Humanos , Afinidad de Anticuerpos/inmunología , Diferenciación Celular/inmunología , Células Plasmáticas/inmunología
4.
bioRxiv ; 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38645147

RESUMEN

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

5.
Adv Healthc Mater ; 13(11): e2303910, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38180445

RESUMEN

Self-assembling protein nanoparticles are a promising class of materials for targeted drug delivery. Here, the use of a computationally designed, two-component, icosahedral protein nanoparticle is reported to encapsulate multiple macromolecular cargoes via simple and controlled self-assembly in vitro. Single-stranded RNA molecules between 200 and 2500 nucleotides in length are encapsulated and protected from enzymatic degradation for up to a month with length-dependent decay rates. Immunogenicity studies of nanoparticles packaging synthetic polymers carrying a small-molecule TLR7/8 agonist show that co-delivery of antigen and adjuvant results in a more than 20-fold increase in humoral immune responses while minimizing systemic cytokine secretion associated with free adjuvant. Coupled with the precise control over nanoparticle structure offered by computational design, robust and versatile encapsulation via in vitro assembly opens the door to a new generation of cargo-loaded protein nanoparticles that can combine the therapeutic effects of multiple drug classes.


Asunto(s)
Nanopartículas , Nanopartículas/química , Animales , Ratones , Proteínas/química , Receptor Toll-Like 8/metabolismo , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/química , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/agonistas
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