Cameron Flayer: If you are interested in neuroimmunology or allergy, this paper is for you

Cameron Flayer, Postdoctoral Research Fellow, Harvard Medical School and Massachusetts General Hospital, shared a post on X:

“I’m elated to share that my postdoc work is now online on nature. If you are interested in neuroimmunology (gd T cells, IL-3, sensory neurons) or allergy (allergic itch and initiation of the allergic immune response), this paper is for you.

In naive individuals, sensory neurons detect allergens upon the first exposure, leading to itch. Concurrently, the release of substance P activates dendritic cells, which traffic to the lymph node and initiate Th2 differentiation (allergic immunity).

We sought to understand why some individuals become sensitized upon their first exposure to an allergen while others tolerate the allergens in their environment. Could there be an endogenous pathway that controls the responsiveness of sensory neurons to allergens.

Using allergic itch as a readout of the allergen responsiveness of sensory neurons, we found that itch to the allergens papain, house dust mite, Alternaria, fire ant, or mosquito saliva depended on the presence of gd T cells.

When we profiled gd T cells in the skin, we were surprised to find not only two well-defined gd T cell subsets (dermal gd T cells and DETCs) but a third subset in the epidermis that lacked the canonical DETC marker Vg5. We termed these cells ‘GD3 cells’.

In many pathways, gd T cells are cytokine machines, so we hypothesized that the allergen-responsiveness of sensory neurons depended on a secreted factor from gd T cells. Interestingly, only stimulated GD3 cell supernatant enhanced allergic itch. So…what are GD3 cells?

We used a variety of assays to show that GD3 cells are transcriptionally distinct from dermal gd T cells and DETCs, are marked by specific variable gamma and delta chains, but particularly Vg4 and Vd4 (Tonegawa nomenclature), and form direct contacts with sensory neurons.

GD3 cells showed transcriptional overlap with human epidermal gd T cells. Epidermal gd T cells in humans are poorly understood because we don’t have a direct equivalent to DETCs. These data suggest that GD3 cells are the true epidermal gd T cell equivalent in humans.

How do GD3 cells promote the allergen responsiveness of sensory neurons? We screened 44 cytokines and chemokines, finding that the only unique factor was IL-3. Sensory neurons, principally of the PEP1 subset, expressed the specific IL-3 receptor Il3ra.

IL-3 from gd T cells promoted allergic itch directly through sensory neuronal Il3ra. Further, IL-3 promoted allergen-induced calcium response in sensory neurons in vitro and in vivo. Thus, gd T cells control the allergen responsiveness of sensory neurons through IL-3.

Downstream of allergic itch is the initiation of the allergic immune response, driven by the release of the neuropeptide substance P. Both dendritic cell migration to the draining lymph node and Th2 differentiation depended on the gd T cell-IL-3 axis.

How does IL-3 promote allergic itch and the initiation of the allergic immune response? JAK2 was required for both outputs, while STAT5 was only required for the immune response. This specificity will be exciting to exploit in the development of novel therapies.

Strikingly, STAT5 bound to the Tac1 (substance P gene) promoter and enhanced the release of substance P upon allergen stimulation. This pathway drove the migration of dendritic cells to the draining lymph node.

Taken together, we describe a pathway upstream of allergen sensitization. If you dive deeper into our data, you’ll see that both genetic and environmental factors influence GD3 cell numbers, explaining why certain individuals are so susceptible to allergen sensitization.

None of this work would have been possible without Caroline Sokol and our other co-authors Peri Matatia, Xueping Zhu, Clive McKimmie (VHIT),Cameron McAlpine, Fil Swirski, Alexandra-Chloé Villani Lab. There are more without X accounts – you can find them on the paper.

I can’t thank Caroline Sokol enough for her mentorship over the last 5 years. I will never forget her advocacy for this work in every way possible and at all hours of the day. She is one of a kind and one of the smartest people I’ve ever met. I can’t recommend her lab more.”

A γδ T cell–IL-3 axis controls allergic responses through sensory neurons

Authors: Cameron H. Flayer, Isabela J. Kernin, Peri R. Matatia, Xiangsunze Zeng, David A. Yarmolinsky, Cai Han, Parth R. Naik, Dean R. Buttaci, Pamela A. Aderhold, Ryan B. Camire, Xueping Zhu, Alice J. Tirard, John T. McGuire, Neal P. Smith, Clive S. McKimmie, Cameron S. McAlpine, Filip K. Swirski, Clifford J. Woolf, Alexandra-Chloe Villani, Caroline L. Sokol.

Source: Cameron Flayer/X