Abstract
Connections between the nervous and immune systems are increasingly recognized as central to brain–body physiology. In this Review, we examine how these systems collaborate to detect and respond to both internal and external stimuli — such as psychological stress, circadian cues, infection, and tissue injury. Rather than operating in isolation, the nervous and immune systems form an integrated network that is more than the sum of its parts. They share a common architecture and vocabulary, enabling bidirectional connection and communication that modulate immune cell characteristics throughout the body. We review immune–nervous interactions within two complementary frameworks: first, a spatial framework that distinguishes communication in the brain, communication within peripheral organs, and communication across distance; and second, a temporal framework that maps nervous system influence across the operational lifespan of the immune system — specifically focusing on how the nervous system impacts immune cell development, distribution, and execution of functions. Finally, we highlight key tools, clinical applications, and questions for future research on how both systems coordinate to respond to somatic and environmental stressors.
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Acknowledgements
A.L. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) no. 559481340. F.K.S. is funded by NHBLI grants P01 HL131478 and 1P01 HL142494. The authors wish to thank all members of the Swirski Lab who provided valuable input during discussions about this review. The authors thank K. Joyes for editing this manuscript.
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Glossary
- Atrioventricular node
-
A collection of cardiomyocytes that electrically connects the heart’s atria and ventricles to coordinate heart beating.
- Blalock’s ‘sixth sense’
-
The concept that the immune system acts like a sensory organ — detecting pathogens and inflammation — and communicates this information to the nervous system via shared signalling molecules.
- Blood–brain barrier
-
The blood–brain barrier (BBB) comprises multiple protective layers including endothelial cells and astrocytes, which play critical roles in regulating permeability and trafficking of cells and molecule between the blood and central nervous system.
- Choline acetyltransferase
-
An enzyme responsible for the synthesis of the neurotransmitter acetylcholine.
- Emergency haematopoiesis
-
A complex state of haematopoiesis consisting of a general expansion of haematopoietic stem and progenitor cells and a shift towards the myeloid lineage common to many inflammatory states.
- Exaptatic adaptations
-
Evolutionary repurposing of existing biological traits for new functions, such as immune molecules co-opted from developmental or metabolic pathways to serve host defence roles.
- Glymphatic system
-
A newly defined brain clearance pathway that is thought to remove waste and deliver nutrients to the brain.
- Inflammatory reflex
-
A neural feedback circuit, mediated by the vagus nerve, that detects and downregulates inflammation.
- Neuroimmune cell units
-
Anatomically distinct micro domains where immune cells and neurons interact to regulate normal the local tissue environment.
- Nucleus accumbens
-
A portion of the ventral striatum that receives dopamine innervation to coordinate responses to rewarding and aversive stimuli.
- Nucleus ambiguus
-
One of the two motor nuclei of the vagus nerve, projecting to internal organs like the heart and the lung.
- Paraventricular nucleus of the hypothalamus
-
Hypothalamic region that integrates neuroendocrine, autonomic and behavioural responses to stress, infection and inflammation by regulating the HPA axis and sympathetic tone.
- Red nucleus
-
A structure in the rostral midbrain involved in motor coordination.
- Suprachiasmatic nucleus
-
(SCN). A small region of the brain in the hypothalamus that is responsible for coordinating circadian rhythms. It receives light inputs from the retina, as well as inputs from other brain regions.
- Thalamus
-
A brain region that serves as a relay station to integrate sensory/motor information between the cortex and brainstem.
- Trained immunity
-
The long-term functional reprogramming of innate immune cells and bone marrow progenitors, which is evoked by exogenous or endogenous insults. It leads to an altered innate immune cell response towards a second challenge after the cell has returned to a non-activated state.
- Vagus nerve
-
The tenth cranial nerve, one of the major components of the parasympathetic nervous system, which regulates organ functions in the head, thoracic and abdominal cavity, and mediates communication between the brain and immune system, including the inflammatory reflex.
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Leunig, A., Gianeselli, M., Russo, S.J. et al. Connection and communication between the nervous and immune systems. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01199-6
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DOI: https://doi.org/10.1038/s41577-025-01199-6
