T1D patient-derived hematopoietic stem cells are programmed to generate Tph, Tfh, and autoimmunity-associated B cell subsets in human immune system mice

Andrea Vecchione, Rachel Madley, Nichole Danzl, Chiara Borsotti, Mohsen Khosravi Marharlooei, Hao Wei Li, Grace Nauman, Xiaolan Ding, Siu Hong Ho, Georgia Fousteri, Megan Sykes

Research output: Contribution to journalArticlepeer-review

Abstract

Interactions between B cells and CD4+ T cells play a central role in the development of Type 1 Diabetes (T1D). Two helper cell subsets, follicular (Tfh) and peripheral (Tph) helper T cells, are increased in patients with T1D but their role in driving B cell autoimmunity is undefined. We used a personalized immune (PI) mouse model to generate human immune systems de novo from hematopoietic stem cells (HSCs) of patients with T1D or from healthy controls (HCs). Both groups developed Tfh and Tph-like cells, and those with T1D-derived immune systems demonstrated increased numbers of Tph-like and Tfh cells compared to HC-derived PI mice. T1D-derived immune systems included increased proportions of unconventional memory CD27IgD B cells and reduced proportions of naïve B cells compared to HC PI mice, resembling changes reported for patients with systemic lupus erythematosus. Our findings suggest that T1D HSCs are genetically programmed to produce increased proportions of T cells that promote the development of unconventional, possibly autoreactive memory B cells. PI mice provide an avenue for further understanding of the immune abnormalities that drive autoantibody pathogenesis and T1D.

Original languageEnglish
Article number109048
JournalClinical Immunology
Volume240
DOIs
Publication statusPublished - Jul 2022
Externally publishedYes

Keywords

  • Autoantibodies
  • Autoimmunity
  • Autoreactive
  • B cell
  • Hematopoietic stem cells
  • Human immune system mice
  • Personalized immune mice
  • T helper follicular cell
  • T peripheral helper cell
  • Type 1 diabetes

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