Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Abstract

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24 hi CD38 hi transitional B cells (TrBs), CD24 hi CD27 + memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-a simultaneously. TrBs had the highest IL-10/TNF-a ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-a increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-a expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-a expression (i.e., reduced IL-10/TNF-a ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-a ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.

Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

“…B cells with regulatory properties are of increasing interest in kidney transplantation, in particular clinical outcomes and phenotypes associated with transitional B cells characterized by surface CD19þCD24hiCD38hi expression (5)(6)(7)(8)(9)(10). This study shows that increased frequencies of these transitional B cells are associated with protection from episodes of BPAR in unselected low/medium immune risk transplant recipients followed longitudinally from the time of transplantation.…”

“…In kidney transplantation, the importance of CD19þCD24hiCD38hi cells is highlighted by patients who are ''tolerant'' to their graft, who display increased frequencies of these cells (5)(6)(7)(8), although proof as to their direct role in this phenomenon is lacking. Following these landmark studies, 2 subsequent casecontrol, cross-sectional investigations (9,10) revealed associations between reduced CD19þCD24hiCD38hi frequencies and transplant rejection, albeit mainly in the context of antibody-mediated rejection (ABMR) many years following transplantation.…”

B Cells, Antibodies, and More

“…Via IL-10 or IL-35, Bregs modulate innate cells, such as DCs, macrophages, or natural killer cells (e.g., decreased IL-6 and IL-12), decrease inflammatory T-cell cytokines, and increase regulatory Tregs, curtailing the ongoing immune response (95,(97)(98)(99)(100)(101). Bregs have also been identified in humans, specifically in the CD24 high CD38 high transitional and CD24 high CD27 1 memory B-cell subsets, and their numbers correlate with better renal transplant outcomes (102)(103)(104). Altered numbers and/ or function of Bregs have been described in SLE and AAV, contributing to disease pathogenesis and/or relapse (102,(105)(106)(107).…”

Regulatory B Cells and Allergy: Uncovering the Link

“…hi immature B cells, which have been described as an important IL-10-secreting Breg subset able to control T-cell inflammation [32][33][34]. Recently, Braza et al [30] showed that this new regulatory B-cell subset, CD9 + Breg cells, inhibits house dust mite-induced allergic airway inflammation.…”