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TLR‐MyD88 signaling blockades inhibit refractory B‐1b cell immune responses to transplant‐related glycan antigens
Author(s) -
Sakai Hiroshi,
Tanaka Yuka,
Tanaka Asuka,
Ohdan Hideki
Publication year - 2021
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.16288
Subject(s) - medicine , immune system , immunology , glycan , refractory (planetary science) , antigen , transplant rejection , cancer research , biology , microbiology and biotechnology , astrobiology , glycoprotein
Refractory B cell responses to T cell–independent (TI) carbohydrate antigens (Ags) are critical drivers of rejection reactions to ABO‐incompatible allogeneic grafts and xenogeneic grafts from other species. To explore the biological significance of crosstalk between Toll‐like receptors (TLRs) and B cell receptors (BCRs) in the TI B cell immunity, we here used MyD88‐, TRIF‐, and α‐galactosyltransferase‐deficient mice to study B cell phenotypes and functional properties during TI transplant–related glycan Ag exposure. BCR stimulation alone induced differentiation into CD5 high (B‐1a) cells, which were highly sensitive to a calcineurin inhibitor (CNI), while co‐stimulation of TLRs and BCRs induced differentiation into CD5 dim (B‐1b) cells in MyD88‐dependent and CNI‐resistant manner. MyD88‐dependent TLR stimulation in B‐1b cells enhanced downstream factors in the BCR‐calcineurin pathway, including a nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). TLR inhibitor together with CNI abrogated refractory B‐1b cell immune responses against the ABO‐blood group Ags, while blocking both BCRs and TLR‐MyD88 by using Bruton's tyrosine kinase inhibitor and histone deacetylase inhibitor abrogated refractory B‐1b cell immune responses against Gal‐glycan Ags. Thus, this study provides a rationale for a novel therapeutic approach to overcome refractory transplant‐related anti‐glycan Ab production by blocking both BCR and TLR‐MyD88 signals.