Regulatory B cells: TIM-1, transplant tolerance, and rejection

Abstract

Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL-10 expression, but also utilizes additional regulatory mechanisms such as TGF-β, FasL, IL-35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker. TIM-1, a broad marker for Bregs first identified in transplant models, plays a major role in Breg maintenance and induction. Here, we expand on the role of TIM-1⁺ Bregs in immune tolerance and propose TIM-1 as a unifying marker for Bregs that utilize various inhibitory mechanisms in addition to IL-10. Further, this review provides an in-depth assessment of our understanding of Bregs in transplantation as elucidated in murine models and clinical studies. These studies highlight the major contribution of Bregs in preventing allograft rejection, and their ability to serve as highly predictive biomarkers for clinical transplant outcomes.

Keywords: Biomarker; Interleukin 10 (IL-10); Regulatory B cells (Bregs); T cell immunoglobulin and mucin domain 1 (TIM-1); Transitional B cells (Tr B cells); Transplantation.

Figure 1

Tim‐1⁺ Breg induction and mechanism of action: Signals through TIM‐1 and the BCR promote expansion of Tim‐1⁺ Bregs and expression of suppressive molecules such as IL‐10, TIGIT and other cytokines and inhibitory receptors. Cognate Breg interactions with T cells suppress inflammatory Th1 and Th17 cell responses, enhance Th2 and Treg (Foxp3 and IL‐10) responses, and reduce subsequent T cell interactions with dendritic cells (DCs). Bregs may also directly interact with DCs and other types of innate cells and suppress their expression of pro‐inflammatory mediators