Stem-like CD4+T Cells in Perivascular Tertiary Lymphoid Structures Sustain Autoimmune Vasculitis

Authors

Yuki Sato
Abhinav Jain
Shozo Ohtsuki
Hirohisa Okuyama
Ines Sturmlechner
Yoshinori Takashima
Kevin-Phu C Le
Melanie C Bois
Gerald J Berry
Kenneth J Warrington
Jörg J Goronzy
Cornelia M Weyand

Publication Date

9-6-2023

Journal

Science Translational Medicine

Abstract

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.

Keywords

Humans, Tertiary Lymphoid Structures, Vasculitis, Arteries, Inflammation, CD4-Positive T-Lymphocytes

Comments

Supplementary Materials

PMID: 37672564