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TIM-4 Identifies IFN-?-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.

ABSTRACT: B cells give rise to polarized subsets, including B effector 1 (Be1) cells and regulatory B cells, which can promote or inhibit immune responses through expression of IFN-? and IL-10, respectively. Such subsets likely explain why B cell depletion can either ameliorate or exacerbate inflammatory diseases; however, these cells remain poorly understood because of the absence of specific markers. Although T cell Ig and mucin domain-containing molecule (TIM)-1 broadly identifies IL-10+ regulatory B cells, no similar markers for Be1 cells have been described. We now show that TIM-4 is expressed by a subset of B cells distinct from those expressing TIM-1. Although TIM-1+ B cells are enriched for IL-10, TIM-4+ B cells are enriched for IFN-?. TIM-1+ B cells enhanced the growth of B16-F10 melanoma. In contrast, TIM-4+ B cells decreased B16-F10 metastasis and s.c. tumor growth, and this was IFN-? dependent. TIM-1+ B cells prolonged islet allograft survival in B-deficient mice, whereas TIM-4+ B cells accelerated rejection in an IFN-?-dependent manner. Moreover, TIM-4+ B cells promoted proinflammatory Th differentiation in vivo, increasing IFN-? while decreasing IL-4, IL-10, and Foxp3 expression by CD4+ T cells-effects that are opposite from those of TIM-1+ B cells. Importantly, a monoclonal anti-TIM-4 Ab promoted allograft tolerance, and this was dependent on B cell expression of TIM-4. Anti-TIM-4 downregulated T-bet and IFN-? expression by TIM-4+ B cells and indirectly increased IL-10 expression by TIM-1+ B cells. Thus, TIM-4+ B cells are enriched for IFN-?-producing proinflammatory Be1 cells that enhance immune responsiveness and can be specifically targeted with anti-TIM-4.

SUBMITTER: Ding Q

PROVIDER: S-EPMC5726915 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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TIM-4 Identifies IFN-γ-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.

Ding Qing Q Mohib Kanishka K Kuchroo Vijay K VK Rothstein David M DM

Journal of immunology (Baltimore, Md. : 1950) 20170828 7

B cells give rise to polarized subsets, including B effector 1 (Be1) cells and regulatory B cells, which can promote or inhibit immune responses through expression of IFN-γ and IL-10, respectively. Such subsets likely explain why B cell depletion can either ameliorate or exacerbate inflammatory diseases; however, these cells remain poorly understood because of the absence of specific markers. Although T cell Ig and mucin domain-containing molecule (TIM)-1 broadly identifies IL-10<sup>+</sup> reg ...[more]

PMID: 28848066

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Project description:Rationale: Corneal transplantation is an effective treatment to corneal blindness. However, the immune rejection imperils corneal allograft survival. An interventional modality is urgently needed to inhibit immune rejection and promote allograft survival. In our previous study, subconjunctival injections of bone marrow-derived mesenchymal stem cells (BM-MSCs) into a rat model of corneal allograft rejection extended allograft survival for 2 d. In this study, we sought to generate IL-10-overexpressing BM-MSCs, aiming to boost the survival-promoting effects of BM-MSCs on corneal allografts and explore the molecular and cellular mechanisms underlying augmented protection. Methods: A population of IL-10-overexpressing BM-MSCs (designated as IL-10-BM-MSCs) were generated by lentivirus transduction and FACS purification. The self-renewal, multi-differentiation, and immunoinhibitory capabilities of IL-10-BM-MSCs were examined by conventional assays. The IL-10-BM-MSCs were subconjunctivally injected into the model of corneal allograft rejection, and the allografts were monitored on a daily basis. The expression profiling of long noncoding RNA (lncRNA) in the allografts was revealed by RNA sequencing and verified by quantitative real-time PCR. The infiltrating immune cell type predominantly upregulating the lncRNA expression was identified by RNAscope in situ hybridization. The function of the upregulated lncRNA was proved by loss- and gain-of-function experiments both in vivo and in vitro. Results: The IL-10-BM-MSCs possessed an enhanced immunoinhibitory capability and unabated self-renewal and multi-differentiation potentials as compared to plain BM-MSCs. The subconjunctivally injected IL-10-BM-MSCs reduced immune cell infiltration and doubled allograft survival time (20 d) as compared to IL-10 protein or plain BM-MSCs in the corneal allograft rejection model. Further, IL-10-BM-MSCs significantly upregulated lncRNA 003946 expression in CD68+ macrophages infiltrating corneal allografts. Silencing and overexpressing lncRNA 003946 in macrophage cultures abolished and mimicked the IL-10-BM-MSCs' suppressing effects on the macrophages' antigen presentation, respectively. In parallel, knocking down and overexpressing the lncRNA in vivo abrogated and simulated the survival-promoting effects of IL-10-BM-MSCs on corneal allografts, respectively. Conclusion: The remarkable protective effects of IL-10-BM-MSCs support further developing them into an effective interventional modality against corneal allograft rejection. IL-10-BM-MSCs promote corneal allograft survival mainly through upregulating a novel lncRNA expression in graft-infiltrating CD68+ macrophages. LncRNA, for the first time, is integrated into an IL-10-BM-MSC-driven immunomodulatory axis against the immune rejection to corneal allograft.

Dataset Information

TIM-4 Identifies IFN-?-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.

Publications

TIM-4 Identifies IFN-γ-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.

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