Chronic T cell proliferation in brains after stroke could interfere with the efficacy of immunotherapies

J Exp Med. 2021 Aug 2;218(8):e20202411. doi: 10.1084/jem.20202411. Epub 2021 May 26.


Neuroinflammation is an emerging focus of translational stroke research. Preclinical studies have demonstrated a critical role for brain-invading lymphocytes in post-stroke pathophysiology. Reducing cerebral lymphocyte invasion by anti-CD49d antibodies consistently improves outcome in the acute phase after experimental stroke models. However, clinical trials testing this approach failed to show efficacy in stroke patients for the chronic outcome 3 mo after stroke. Here, we identify a potential mechanistic reason for this phenomenon by detecting chronic T cell accumulation-evading the systemic therapy-in the post-ischemic brain. We observed a persistent accumulation of T cells in mice and human autopsy samples for more than 1 mo after stroke. Cerebral T cell accumulation in the post-ischemic brain was driven by increased local T cell proliferation rather than by T cell invasion. This observation urges re-evaluation of current immunotherapeutic approaches, which target circulating lymphocytes for promoting recovery after stroke.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autopsy
  • Brain / immunology*
  • Brain / pathology*
  • Brain Ischemia / drug therapy
  • Brain Ischemia / immunology
  • Brain Ischemia / pathology
  • Cell Proliferation
  • Female
  • Humans
  • Immunotherapy*
  • Integrin alpha4 / immunology
  • Lymphocyte Count
  • Male
  • Mice, Inbred C57BL
  • Natalizumab / pharmacology
  • Natalizumab / therapeutic use
  • Neuronal Plasticity / drug effects
  • Recovery of Function / drug effects
  • Stroke / immunology*
  • Stroke / physiopathology
  • Stroke / therapy*
  • T-Lymphocytes / immunology*


  • Natalizumab
  • Integrin alpha4