Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Deng, Shaoping; Moore, Daniel J.; Huang, Xiaolun; Lian, Moh-Moh; Mohiuddin, Muhammad M.; Velededeoglu, Ergun; Lee, Major K.; Sonawane, Samsher; Kim, James; Wang, Jing; Chen, Haiying; Corfe, Steven A.; Paige, Christopher J.; Shlomchik, Mark J.; Caton, Andrew J.; Markmann, James F.

doi:10.4049/jimmunol.178.10.6028

Cited by 90 publications

(93 citation statements)

References 22 publications

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“…Further studies will be necessary to determine whether these cells are truly associated with tolerance after renal transplantation, and, if so, whether they play a causative role and by what mechanism they do so. A potential role for B cells in transplantation tolerance is consistent with recent reports demonstrating a role for regulatory B cells in murine models of chronic inflammation (40)(41)(42), autoimmune inflammation induced by apoptotic cells (43), and transplant tolerance induced by treatment with antibody to CD45RB (44). As suggested by these and other studies, it remains to be determined whether B cells possess direct regulatory properties or act through the production of regulatory cytokines or antibodies (41,42).…”

Section: Figuresupporting

confidence: 70%

Identification of a B cell signature associated with renal transplant tolerance in humans

et al. 2010

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Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.

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Section: Figuresupporting

confidence: 70%

Identification of a B cell signature associated with renal transplant tolerance in humans

et al. 2010

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“…39,[44][45][46][47] It must be stressed that B cells play a critical role in these processes. 48 Therefore additional studies into the impact of CD45RB ligation on the surface of B cells are needed. From our findings, future therapies targeting RB are likely to influence peripheral B-cell developmental, receptor-mediated selection, and SHM induction/termination.…”

Section: Discussionmentioning

confidence: 99%

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Jackson

Harp

Patel

et al. 2009

Blood

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We previously reported that RO ؉ expression correlated with increased mutation, activation, and selection among human germinal center (GC) B cells. Here, we subdivided human tonsillar B cells, including IgD ؊ CD38 ؉ GC B cells, into different fractions based on RB expression. Although each subset contained RB ؉ cells, when used as an intrasubset marker, differential RB expression effectively discriminated between phenotypically distinct cells. For example, RB ؉ GC B cells were enriched for activated cells with lower AID expression. RB inversely correlated with mutation frequency, demonstrating a key difference between RB-and RO-expressing GC B cells. Reduced RB expression during the transition from pre-GC (IgM ؉ IgD ؉ CD38 ؉ CD27 ؊ ) to GCB cells was followed by a dramatic increase during the GC-to-plasmablast (IgD ؊ CD38 ؉؉ CD27 ؉ ) and memory (IgD ؊ CD38 ؊ CD27 ؉ ) transition. Interestingly, RB ؉ GC B cells showed increased signs of terminal differentiation toward CD27 ؉ post-GC early plasmablast (increased CD38 and RO) or early memory IntroductionImmune function is uncompromisingly governed by at least 3 interdependent principles including recognition, effector function, and transition. Early naive B and T cells that successfully bind foreign antigen become activated and undergo developmental transition toward more mature, faster responding memory subsets. In contrast, lymphocytes that bind self-antigen in the periphery are usually counterselected against and undergo a different type of transition, one toward apoptosis or anergy. Ineffectual negative selection against self-specific B cells has been associated with the development of autoimmune and neoplastic diseases. Unfortunately, potential factors responsible for the redirection or abrogation of transitions toward cell death and anergy have not been conclusively determined. Antibody sequence analyses revealed that B cells participating in autoreactive responses are often mutated and show signs of selection for self-antigen. 1,2 This suggests that somatic hypermutation (SHM) during proliferation and activationbased transitions in the dynamic germinal center reaction may play a role (whether direct or indirect) in disease pathogenesis.We therefore sought to develop an expedient approach that would allow for the reproducible identification of B-cell populations that exist at different transitional stages based on their states of activation, SHM-dependent diversification, and developmental progression toward adjacent downstream subsets. Delineating how surface marker profiles change as B cells transition between key stages (especially when immunoregulatory markers such as CD45 protein tyrosine phosphatase are included in such profiles) should increase our understanding of B-cell development and ultimately how to circumvent dysregulated processes that could lead to disease.Over the past 3 decades, our research laboratory has investigated multiple aspects of human B-cell development and the molecular processes that collectively shape the peripheral BCR repertoi...

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“…More recently, the role of B cells as APC has been revisited. Antigen presentation by B cells has been shown to induce tolerance [24,31], and resting B cells are known to play essential roles in transplantation tolerance and tolerance against tumors in a MHC-class II dependent manner [32][33][34]. Unlike DC, B cells are APC that do not constitutively express high levels of co-stimulatory molecules like MHC class II and B7 [35].…”

Section: Discussionmentioning

confidence: 99%

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Shah

Qiao

2008

Eur J Immunol

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Regulatory T cells (Treg) play critical roles in maintaining tolerance and preventing autoimmunity. It is not fully clear how these cells are generated and maintained. Here, we show that resting B cells are able to expand Treg. This expansion requires TGF-b3 and signaling through the TCR and CD28. Upon activation, B cells express less TGF-b3, which reduces their capacity to expand Treg and which also results in increased Treg death. This may ensure that B cells can function as potent professional antigen presenting cells during infections. However, in the absence of any infection, we find that B-cell-deficient lMT mice have decreased percentages of Treg in the periphery. Our data suggest that resting B cells, which may be presenting self-antigens to T cells, can expand and maintain specific Treg and thus might be involved in the prevention of autoimmunity. Key words: B cells . Regulatory T cells . Tolerance Supporting Information available online IntroductionRegulatory T cells (Treg) are a subset of T cells that can actively suppress innate as well as adaptive immunity and have been implicated in self-tolerance, autoimmunity, cancer, transplantation immunology and a myriad of infectious diseases [1][2][3][4][5][6]. There are numerous different subsets of Treg based on their phenotypic markers, amonge which the naturally occurring Treg (nTreg) population is well studied and characterized. nTreg are a subset of CD4 1 T cells expressing CD25 and the transcription factor Forkhead box protein 3 (Foxp3). Foxp3 has been shown to be the master regulator for the generation of nTreg. Although Foxp3 À/À mice lack CD4 1 CD25 1 T cells, expression of Foxp3 in CD4 1 CD25 -T cells is sufficient for converting them into CD4 1 CD25 1 T cells with suppressive function [7,8].CD4 1 CD25 1 Foxp3 1 Treg arise in the thymus and enter into the periphery where they constitute $5-10% of the CD4 1 T cells. nTreg generation in the thymus is thought to require high-affinity peptide-MHC class II interactions in contrast to low-affinity peptide-MHC class II interactions required for positive selection of conventional CD4 1 T cells [9,10]. There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-r...

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Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Cited by 90 publications

References 22 publications

Identification of a B cell signature associated with renal transplant tolerance in humans

Identification of a B cell signature associated with renal transplant tolerance in humans

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

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Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Cited by 90 publications

References 22 publications

Identification of a B cell signature associated with renal transplant tolerance in humans

Identification of a B cell signature associated with renal transplant tolerance in humans

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

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Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3