Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis.

in Immunity by Carina Diehl, Valeria Soberón, Seren Baygün, Yuanyan Chu, Jonathan Mandelbaum, Laura Kraus, Thomas Engleitner, Martina Rudelius, Marco Fangazio, Christoph Daniel, Sabrina Bortoluzzi, Sabine Helmrath, Pankaj Singroul, Vanessa Gölling, Francisco Osorio Barrios, Gönül Seyhan, Lena Oßwald, Maike Kober-Hasslacher, Theodor Zeng, Rupert Öllinger, Ali M Afzali, Thomas Korn, Mohsen Honarpisheh, Maciej Lech, Qurrat Ul Ain, Joachim Pircher, Vanna Imširović, Vedrana Jelenčić, Felix M Wensveen, Verena Passerini, Stefanie Bärthel, Govind Bhagat, David Dominguez-Sola, Dieter Saur, Katja Steiger, Roland Rad, Laura Pasqualucci, Oliver Weigert, Marc Schmidt-Supprian

TLDR

  • A new study shows that T cells play a crucial role in regulating B cells' behavior to prevent autoimmune diseases and lymphoma.
  • T cells target overactive B cells to prevent them from causing harm, helping to maintain a healthy balance in the immune system.
  • This breakthrough could lead to new treatments for autoimmune diseases and lymphoma.

Abstract

B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.

Overview

  • The study investigates the interplay between autoimmunity and lymphoma risk factors centered around the negative immune regulator TNFAIP3/A20 in mice.
  • The researchers found that B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not.
  • The study aimed to identify the mechanisms underlying this paradox and define a permissive window for autoimmunity to emerge.

Comparative Analysis & Findings

  • Cytotoxic T cells recognized and targeted B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared.
  • Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation.
  • The study identified a rheostat-like cytotoxic T cell checkpoint that instructed and directed cytotoxicity against hyperresponsive B cells.

Implications and Future Directions

  • The study highlights the importance of T cell-mediated negative feedback control in regulating inherited and acquired B cell pathogenicity.
  • The findings suggest that investigating the mechanisms underlying the interplay between T cells and B cells may provide valuable insights into the development of autoimmune diseases.
  • Future studies could explore the therapeutic potential of T cell-targeted therapies in autoimmune diseases and lymphoma treatment.
Read Full Article