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- Title
CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.
- Authors
Muthana, Musleh M.; Xuexiang Du; Mingyue Liu; Xu Wang; Wei Wu; Chunxia Ai; Lishan Su; Pan Zheng; Yang Liu
- Abstract
Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA- 4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA- 4 ADC). The anti-CTLA- 4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF- alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.
- Subjects
REGULATORY T cells; REGULATORY B cells; B cells; T cells; ANTIBODY-drug conjugates; CYTOTOXIC T lymphocyte-associated molecule-4; IMMUNOLOGIC memory; T cell receptors
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.87281