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Hiltensperger, Michael; Beltran, Eduardo; Kant, Ravi; Tyystjarvi, Sofia; Lepennetier, Gildas; Moreno, Helena Dominguez; Bauer, Isabel J.; Grassmann, Simon; Jarosch, Sebastian; Schober, Kilian; Buchholz, Veit R.; Kenet, Selin; Gasperi, Christiane; Ollinger, Rupert; Rad, Roland; Muschaweckh, Andreas; Sie, Christopher; Aly, Lilian; Knier, Benjamin; Garg, Garima; Afzali, Ali M.; Gerdes, Lisa Ann; Kumpfel, Tania; Franzenburg, Soren; Kawakami, Naoto; Hemmer, Bernhard; Busch, Dirk H.; Misgeld, Thomas; Dornmair, Klaus and Korn, Thomas (2021): Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. In: Nature Immunology, Vol. 22, No. 7: pp. 880-892

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Korn and colleagues demonstrate that the site of T cell priming (gut versus skin draining lymph nodes) dictates their effector phenotypes and homing to distal sites of immunopathology. Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6(+), and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.

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