Decoding the neuroimmune control of cutaneous gamma/delta cell function in allergic immunity

The National Institute of Allergy and Infectious Diseases awarded Massachusetts General Hospital $776,034 on February 9, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to decode the neuroimmune control of cutaneous gamma-delta T cell function in allergic immunity.

The research investigates a bidirectional neuroimmune circuit involving sensory neurons and epidermal gamma-delta T cells (GD3S) in allergic skin responses. The study integrates cellular immunology, neurobiology, and molecular biology approaches across three specific aims: evaluating chemokine-mediated pathways driving cutaneous GD3 localization, determining neuronal factors driving GD3 function, and identifying corresponding human immune correlates. Central to the hypothesis is that sensory neurons sustain GD3S and human epidermal T cells through ligand-receptor interactions, with preliminary findings showing that peptidergic neurons express CCL8 and BDNF while GD3S express corresponding receptors CCR8 and NTRK2. The research aims to elucidate mechanisms regulating GD3 maintenance and function in both model organisms and humans to inform understanding of allergic disease pathogenesis.

Performance occurs at Massachusetts General Hospital's Research Management Division in Boston, Massachusetts, with a period of performance from February 9, 2026 through January 31, 2031. The assistance type is a Project Grant, classified as R01.

Abstract

Allergic diseases result from dysregulated type-2 immune responses to environmental allergens, with sensory neurons playing a key role in both allergen detection and immune activation. Sensory neurons, specifically TRPV1+ peptidergic (PEP) neurons, detect protease allergens, triggering itch and releasing substance p, which activates dendritic cells to initiate type-2 immunity. Recent findings reveal a bidirectional neuroimmune circuit involving sensory neurons and a subset of epidermal  t cells, termed GD3S, which produce IL-3. GD3S reside near free nerve endings, where their IL-3 primes IL3RA-expressing PEP1 neurons to enhance allergen detection and promote allergic immunity. Our long-term goal is to elucidate the mechanisms that regulate GD3 maintenance and function in both model organisms and humans. Type-2 immunity depends on feedback loops between sensory and immune cells that amplify allergic inflammation. Our central hypothesis is that sensory neurons not only respond to IL-3, but also sustain murine GD3S and their human counterparts - epidermal  t cells - through ligand-receptor interactions. Supporting this, we find that PEP1 neurons express CCL8 and bdnf, while GD3S express the corresponding receptors CCR8 and NTRK2, respectively. GD3S depend on CCR8 for localization and proliferate in response to bdnf, suggesting that neurons actively regulate GD3 positioning and function. Furthermore, we find that human epidermal  t cells share common transcriptional signatures with murine GD3S, suggesting that epidermal  t cells may serve as the human correlate of GD3S. To test our central hypothesis, we will integrate cellular immunology, neurobiology, and molecular biology approaches across three specific aims: (1) evaluate the chemokine-mediated pathways driving cutaneous GD3 localization, (2) determine the neuronal factors driving GD3 function, and (3) identify the human equivalent of GD3 cells. These studies will establish a fundamental understanding of the neuroimmune interactions that drive allergic immune activation, laying the foundation for therapeutic strategies to prevent allergic sensitization, treat chronic itch, and target chronic allergic inflammatory disorders.