How tissue-specific unconventional T cells shape local immune responses

A pioneering study published in Immunity today reveals how tissue-specific unconventional T cells travel via lymphatic pathways to lymph nodes, where they orchestrate customized immune responses. This breakthrough has profound implications for targeted vaccination and immunotherapy strategies.
Evolutionary forces shape local tissue contexture. Beilhack lab, Immunotherapy for inflammation, cancer and infections, Würzburg Systems Immunology, Germany

Local environments shape specialized immune responses. (A) Darwin’s Gapagos finches revealed how natural selection drives the adaptation of species to their environments. (B) Similarly, unconventional T cells—including invariant natural killer T (iNKT) cells, gamma delta T (γδ-T) cells, and mucosal-associated invariant T (MAIT) cells— adapt to specific peripheral organ microenvironments. As these immune cells migrate from lungs, small intestines, or the skin to the corresponding draining lymph nodes, they execute immune functions precisely adapted to the local tissue requirements.

Unconventional T cells, including invariant natural killer T cells, gamma delta T cells, and mucosal-associated invariant T cells, differ from conventional T cells by engaging in broader immune surveillance and responding to diverse signals, such as stress signals, lipid antigens, or metabolites.

“Our study demonstrates that local forces guide unconventional T cells from tissues to lymph nodes, where they imprint tissue-specific characteristics,” explains our collaboration partner Prof. Wolfgang Kastenmüller, who lead the international research team.” Dendritic cells have long been known to relay information from peripheral tissues to draining lymph nodes, initiating immune responses. However, it’s now evident that dendritic cells are not solely responsible for this crucial flow of information.  Each tissue harbors unique subtypes of unconventional T cells, influencing the composition and function of T cells in nearby lymph nodes.”

This diversity leads to varied immune responses within lymph nodes, where unconventional T cells form interconnected functional units across different T cell receptor-based lineages. These units are crucial for shaping both innate and adaptive immune responses tailored to the specific tissues drained by each lymph node.

Implications for Future Research and Medicine

Understanding how unconventional T cells migrate and function in lymph nodes is pivotal for advancing immunology and medical practice. Leveraging our insights allows scientists to enhance tissue-specific immune responses, paving the way for precision vaccination and immunotherapy approaches with reduced side effects. This progress holds promise for personalized medicine, facilitating more effective treatments that meet individual patient needs while minimizing adverse effects.

This interdisciplinary research project was led by Prof. Wolfgang Kastenmüller at Würzburg’s Institute for Systems Immunology at the Julius-Maximilians-University Würzburg, in collaboration with groups from the Würzburg Helmholtz Institute for RNA-based Infection Research (HIRI), the JMU Institute for Molecular Infection Biology (IMIB), the Centre d’Immunologie de Marseille-Luminy (CIML), and our team at the Department of Medicine II at Würzburg University Hospital. Financial support was provided by IZKF Würzburg, the German Research Foundation (DFG), the European Research Council (ERC), and the Max Planck Society.

For more information, visit the press release in German.

Publication Reference:

Ataide MA*, Knöpper K*, Cruz de Casas P*, Ugur M, Eickhoff S, Zou M, Shaikh H, Trivedi A, Grafen A, Yang T, Prinz I, Ohlsen K, Gomez de Agüero M, Beilhack A, Huehn J, Gaya M, Saliba AE, Gasteiger G, Kastenmüller W. (2022). Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Immunity, 55(10):1813-1828.e9.

This research article was also highlighted in Immunity by Emily Thornton and Tal Arnon: “It takes a village to skew a lymph node.