Early Life Imprinting of Intestinal Immune Tolerance and Tissue Homeostasis

Yoselin A. Paucar Iza and Chrysothemis C. Brown

Immunological Reviews. 2024. doi: 10.1111/imr.13321

A review of mechanisms underlying the early life window for immune tolerance to the microbiota with a focus on newly identified Thetis cells.

Thymic Mimicry: The Art of Imitation

Vanja Cabric and Chrysothemis C. Brown

Journal of Experimental Medicine. 2023. doi: 10.1084/jem.20231010

Display of tissue self-antigens within the thymus is critical for the regulation of self-reactive T cells. Recently described thymic mimetic cells provide a previously unappreciated source of tissue self-antigens; however, the cues that drive their differentiation and the role of mimetic cells in peripheral tolerance are relatively unexplored. In this issue of J. Exp. Med., Michelson et al. identify a role for Hnf4g in entero-hepato mimetic cell differentiation, as well as peripheral M cells.

SEACells Infers Transcriptional and Epigenomic Cellular States From Single-Cell Genomics Data.

Persad S, Choo Z, Dien C, Sohail N, Masilionis I, Chaligné R, Nawy T, Brown C, Sharma R, Pe'er I, Setty M, Pe'er D. Nat Biotech 2023

Nature Biotechnology. 2023. doi: 10.1038/s41587-023-01716-9

Spatiotemporal Regulation of Peripheral T cell Tolerance

Chrysothemis C. Brown and Alexander Y. Rudensky

Science. 2023. doi: 10.1126/science.adg6425

A review of current advances in peripheral T cell tolerance with a focus on intestinal tolerance to the gut microbiota and mechanisms underlying developmental windows for immune tolerance.

Novel Antigen-Presenting Cell Imparts T-reg Dependent Tolerance to Gut Microbiota

Blossom Akagbosu†, Zakieh Tayyebi†, Gayathri Shibu, Yoselin Paucar Iza, Deeksha Deep, Yollanda Parisotto, Logan Fisher, H. Amalia Pasolli, Valentin Thevin, Rasa Elmentaite, Maximilian Knott, Saskia Hemmers, Lorenz Jahn, Christin Friedrich, Jacob Verter, Zhong-Min Wang, Marcel van den Brink, Georg Gasteiger, Thomas G. P. Grünewald, Julien C. Marie, Christina Leslie, Alexander Y. Rudensky*, Chrysothemis C. Brown*

Nature. 2022. doi:10.1038/s41586-022-05309-5

Establishing tolerance to the gut microbiota is critical to prevent autoimmune and inflammatory disease. Peripherally generated Treg cells suppress immune responses against commensal microbes; however, the antigen-presenting cell type that instructs the differentiation of peripheral Treg cells is not known. We identified a novel lineage of antigen presenting cells (Thetis cells; TCs), enriched in gut lymph nodes during early life, and demonstrated an essential role for TCs in pTreg cell differentiation and intestinal tolerance.

Assembly of a Spatial Circuit of T-bet Expressing T and B Lymphocytes is Required for Antiviral Humoral Immunity

Alejandra Mendoza, Teddy Yewdell, Beatrice Hoyos, Michail Schizas, Regina Bou-Puerto, Anthony J. Michaels, Chrysothemis C. Brown, Jayanta Chaudhuri, Alexander Y. Rudensky

Science Immunology. 2021. doi: 10.1126/sciimmunol.abi4710

Protective humoral immunity against viral infections requires an effective type 1 immune response by germinal center (GC) T and B cells, a hallmark of which is expression of the transcription factor T-bet. Mendoza et al. demonstrate that the activity of T-bet+ T and B cells are spatiotemporally coordinated to control distinct features of the humoral response to viral infection.

Volume Control: Turning the Dial on Regulatory T cells

Chrysothemis C. Brown, Rachel A. Gottschalk

Cell. 2021. doi: 10.1016/j.cell.2021.06.015

Treg-mediated immunosuppression must be tightly regulated to support immunity while limiting tissue damage. In this issue of Cell, Wong et al. and Marangoni et al. use high-resolution imaging to define feedback circuits that quantitatively control local Treg expansion and function.

Conceiving the Inconceivable: The Function of Aire in Immune Tolerance to Peripheral Tissue-Restricted Antigens in the Thymus

Chrysothemis C. Brown, Alexander Y. Rudensky

J Immunol. 2021. https://doi.org/10.4049/jimmunol.2001285

Pillars of Immunology commentary on “Projection of an Immunological Self Shadow within the Thymus by the Aire Protein” describing investigations into immunological tolerance culminating in the landmark paper from the Mathis and Benoist laboratory that identified AIRE as essential for a subset of thymic epithelial cells to present peripheral tissue Ags to developing T cells, thereby preventing pathogenic, self-reactive T cells from leaving the thymus.

PD-L1 Blockade Therapy: Location, Location, Location.

Chrysothemis C. Brown, Jedd D. Wolchok. 

Cancer Cell. 2020. https://doi.org/10.1016/j.ccell.2020.10.017

The mechanisms by which PD-1/PD-L1 inhibition elicits anti-tumor immunity are not fully understood. In this issue of Cancer Cell, Dammeijer et al. address the role of PD-L1 inhibition specifically within the tumor-draining lymph node, identifying a potential role for PD-L1 expressing dendritic cells within the lymph node in regulation of anti-tumor immune responses.

Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity.

Chrysothemis C Brown*†, Herman Gudjonson*, Yuri Pritykin, Deeksha Deep, Vincent-Philippe Lavallée, Alejandra Mendoza, Rachel Fromme, Linas Mazutis, Charlotte Ariyan, Christina Leslie, Dana Pe'er, Alexander Y Rudensky†  

Cell. 2019. https://doi.org/10.1016/j.cell.2019.09.035.

Classical dendritic cells are divided into cDC1s and cDC2s. The transcription factors that regulate the development and function of cDC2s are largely unknown, limiting our ability to target these cells and determine their role in immune responses. We identified two cDC2 lineages defined by unique transcription factor networks with distinct anti- and pro-inflammatory phenotypes. Lineage-defining transcription factor networks and signature gene expression programs were conserved across mouse and human. This discovery advances our understanding of DC biology and will be critical for successful manipulation of DCs in cancer immunotherapy, vaccination and autoimmunity.

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

Frank Penkava, Martin Del Castillo Velasco-Herrera, Matthew D. Young, Nicole Yager, Lilian N. Nwosu, Arthur G. Pratt, Alicia Lledo Lara, Charlotte Guzzo, Ash Maroof, Lira Mamanova, Suzanne Cole, Mirjana Efremova, Davide Simone, Andrew Filer, Chrysothemis C. Brown, Andrew L. Croxford, John D. Isaacs, Sarah Teichmann, Paul Bowness, Sam Behjati & M. Hussein Al-Mossawi

Nature Communications. 2020. https://doi.org/10.1038/s41467-020-18513-6

Repurposing a novel anti-cancer RXR agonist to attenuate acute GVHD and maintain graft-versus-leukemia responses 

Govindarajan Thangavelu, Chao Wang, Michael Loschi, Asim Saha, Mark Osborn, Scott N Furlan, Kazutoshi Aoyama, Cameron McDonald-Hyman, Ethan G Aguilar, Amanda S Janesick, Roshantha A Chandraratna, Yosef Refaeli, Angela Panoskaltsis-Mortari, Kelli P. MacDonald, Geoffrey R. Hill, Robert Zeiser, Ivan Maillard, Jonathan Serody, William J. Murphy, David H. Munn, Bruce Blumberg, Chrysothemis Brown, Vijay K Kuchroo, Leslie S Kean, Keli Hippen, Randolph J Noelle, Bruce R. Blazar 

Blood. 2020.  https://doi.org/10.1182/blood.2020005628

Enforcing T cell innocence

Chrysothemis C. Brown, Alexander Y. Rudensky

Science. 2020. https://doi.org/10.1126/science.aaz7741

The adaptive immune system, with T and B lymphocytes being its two principal cell types, enables efficient protection from countless pathogens. T lymphocytes emerge from the thymus as quiescent naïve cells and display an immense repertoire of clonally distributed T cell receptors (TCRs) that detect antigens and are generated as the result of a largely random process of somatic gene rearrangement in thymic precursor cells. On page 264 of this issue, ElTanbouly et al. show that naïve T cell quiescence is actively regulated upon their egress from the thymus and that this may be critical for constraining self-reactive T cells and preventing autoimmunity.

Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program.

Chrysothemis C.Brown, Daria Esterhazy, Aurelien Sarde, Mariya London, Venu Pullabhatla, Ines Osma-Garcia, Raya al-Bader, Carla Ortiz, Raul Elgueta, Matthew Arno, Emanuelede Rinaldis, Daniel Mucida, Graham M.Lord, Randolph J.Noelle

Immunity. 2015. https://doi.org/10.1016/j.immuni.2015.02.003

Vitamin A is critical for T cell mediated immunity; however, the underlying mechanisms were not known. We report a key role for the Vitamin A metabolite, retinoic acid (RA), in sustaining Th1 lineage commitment. We demonstrate that RA activates enhancers to establish the Th1 epigenome and prevent conversion to pathogenic Th17 cells. This work identified RA/RARα as a therapeutic target for the treatment of Th17 mediated autoimmunity or enhanced Th1 responses during vaccination and tumor immunotherapy.

Mapping autoimmune disease epigenetics: what's on the horizon?

Chrysothemis C. Brown, Lucy R. Wedderburn

Nat Rev Rheumatol. 2014. https://doi.org/10.1038/nrrheum.2014.210