Tissue Lymphocyte Niches

One area of research focus is to understand the tissue niches which support and regulate type 2 lymphocytes, including group 2 innate lymphoid cells (ILC2), Th2 tissue-resident memory cells, and type 2-skewed Tregs, each of which is associated with allergic/type 2 beneficial and pathologic inflammation. We have identified specific micro-anatomic sites where these type 2 lymphocytes preferentially reside and are continuing to characterize these sites of immune-tissue cross-talk across a range of healthy and perturbed organs and conditions.

We previously defined a conserved microanatomical cross-tissue niche for ILC2, predominantly localized to adventitial cuffs, the outermost layer of larger blood vessels and other tubular or border structures, including airways and fascial tissue planes. Adventitial cuffs are dynamic spaces enriched with extracellular matrix components, small blood vessels, lymphatics, nerves, and immune cells. Within this microanatomical site, ILC2 are intimately associated with adventitial fibroblasts, a population with similarities to previously described mesenchymal stromal cell subsets. Lung adventitial fibroblasts produce Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) and are key local regulators of ILC2 and type 2 immunity. Reciprocally, ILC2 support adventitial fibroblast expansion and inflammatory gene expression, including IL-33. We hope that continued study of these dynamic tissue sites will lead to a better understanding of type 2 lymphocyte interaction with fibroblasts and other immune cell populations within their discrete microanatomical niche and how adventitial immune responses are regulated to impact the physiology of their host tissue.

We also continue to work on the cross-regulation of type 1 lymphocytes that produce IFNg, type 2 lymphocytes that produce IL-5/IL-13, and type 3/17 lymphocytes that produce IL-17 and IL-22. We have found that IFNg signaling on type 2 lymphocytes impairs their function at multiple levels, including their ability to expand beyond traditional adventitial niches. We continue to explore the nature of these lymphocyte-driven cross-regulations in models of infection and fibrosis.