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Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity.

Abstract (Expand)

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.

Authors: M. Hiltensperger, E. Beltran, R. Kant, S. Tyystjarvi, G. Lepennetier, H. Dominguez Moreno, I. J. Bauer, S. Grassmann, S. Jarosch, K. Schober, V. R. Buchholz, S. Kenet, C. Gasperi, R. Ollinger, R. Rad, A. Muschaweckh, C. Sie, L. Aly, B. Knier, G. Garg, A. M. Afzali, L. A. Gerdes, T. Kumpfel, S. Franzenburg, N. Kawakami, B. Hemmer, D. H. Busch, T. Misgeld, K. Dornmair, T. Korn

Date Published: 9th Jun 2021

Publication Type: Journal

Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity.

Abstract (Expand)

Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre … recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer's disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.

Authors: C. Fecher, L. Trovo, S. A. Muller, N. Snaidero, J. Wettmarshausen, S. Heink, O. Ortiz, I. Wagner, R. Kuhn, J. Hartmann, R. M. Karl, A. Konnerth, T. Korn, W. Wurst, D. Merkler, S. F. Lichtenthaler, F. Perocchi, T. Misgeld

Date Published: 11th Sep 2019

Publication Type: Journal

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