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TIM-4 Identifies Proinflammatory B Cells Expressing an IL-23-Driven “Proinflammatory Module”

Q. Ding1, V. Sola1, D. Rothstein2

1University of Pittsburgh, Pittsburgh, PA, 2Thomas E Starzl Transplant Institute, Pittsburgh, PA

Meeting: 2022 American Transplant Congress

Abstract number: 279

Keywords: Anergy, Angiography, Antibodies, Antigenemia

Topic: Basic Science » Basic Science » 04 - B-cell / Antibody /Autoimmunity

Session Information

Session Name: B-cell / Antibody /Autoimmunity

Session Type: Rapid Fire Oral Abstract

Date: Monday, June 6, 2022

Session Time: 3:30pm-5:00pm

 Presentation Time: 3:30pm-3:40pm

Location: Hynes Room 310

*Purpose: B cells play important Ab-independent roles promoting or inhibiting immune responses through the opposing activity of Bregs and poorly understood effector B cells (Beff) which express proinflammatory cytokines. TIM-1 signals underlie expression of a “regulatory module” in Bregs that includes suppressive cytokines and co-inhibitors. However, there is no unifying phenotypic or functional marker for Beff, and regulation and extent of their inflammatory repertoire is unknown.

*Methods: Highly purified TIM-4+ B cells were prepared by flow cytometric cell sorting. RNAseq analysis was performed on sort-purified WT TIM-4+ vs. TIM-4− B cells stimulated with anti-IgM+IL-23. IL-10, IFN-g, IL-17 were examined by flow cytometric intracellular staining. IL-17 was also examined by q-RT-PCR. Mice islets transplantation.

*Results: We have shown that TIM-4+ B cells are enriched for IFNγ and accelerate islet allograft rejection. We now show that TIM-4+ B cells also express IL-17. While transfer of WT TIM-4+ B cells into syngeneic μMT (B6) recipients of BALB/c islets shortens graft survival (GS), transfer of TIM-4+ B cells from IL-17KO mice induces tolerance (80% of recipients). Moreover, recipient mice with an inducible B cell-specific deletion of RORγt (essential for IL-17), exhibit 30% long-term GS. CD4 and CD8 T cells in such mice have ↑ Tregs and ↓ IL-17 and IFNγ. Thus, IL-17KO B cells exhibit potent suppression. Of note, loss of B cell IL-17 (or IL-17RA) resulted in dysregulated TIM-4+ B cells that overexpress IL-10. Yet RORγt-/- B cells lacking IL-10 still promoted tolerance, indicating that B cell IL-17 is a potent driver of graft rejection. To identify factors that augment B-cell IL-17 expression, B cells from IL-17A-GFP reporter mice were stimulated 24h in vitro with anti-IgM plus IL-1β, IL-6, IL-21, or IL-23. IL-23 was the most potent inducer of GFP. qRT-PCR confirmed that anti-IgM+IL-23 induced IL-17a mRNA in TIM-4+ but not TIM-4- B cells. Finally, we performed RNAseq on purified WT TIM-4+ vs. TIM-4− B cells stimulated with anti-IgM+IL-23. Of 45,519 genes detected, 21were downregulated in TIM-4+ B cells, while 1136 were upregulated (p ≤0.05, Fold-change ±2). In addition to upregulation of IL17a(20x), IL17f(30x), and IFNg(8x), TIM-4+B cells also highly express many other proinflammatory cytokine genes (e.g., IL22(50x), IL1b(27x), IL6(4x), IL12b(17x), and IL21. TIM-4+B cells also highly expressed a panel of other immune modulators including Il1r1, Icos, Fasl, Tlr2, Ccl5, Ccl9, Ccl6 Ccl2, Ccl1, Cxcl3, Cxcl1, Cxcl2, Cxcl12, Il12rb1, Cd80 – associated with inflammation and autoimmunity.

*Conclusions: Our data suggest that B cell IL-17 is a potent mediator of the alloimmune response. Moreover, TIM-4+ Beff promote allograft rejection through expression of a pro-inflammatory module driven by IL-23 and maintained by IL-17. This enhances our understanding of Beff biology and provides insights highly relevant to immune tolerance.

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To cite this abstract in AMA style:

Ding Q, Sola V, Rothstein D. TIM-4 Identifies Proinflammatory B Cells Expressing an IL-23-Driven “Proinflammatory Module” [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/tim-4-identifies-proinflammatory-b-cells-expressing-an-il-23-driven-proinflammatory-module/. Accessed May 28, 2025.

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