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Immunoregulatory Potential of T2-MZP B Cells

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Immunoregulatory Potential of T2-MZP B Cells For reprint orders, please contact: REVIEW [email protected] Immunoregulatory potential of T2-MZP B cells Paul A Blair, B cells with the capacity to inhibit inflammatory immune responses have now been Michael R Ehrenstein described in a number of experimental models of autoimmunity, infection and cancer. Just & Claudia Mauri† as the identification of regulatory T cells offers a possible target for the control of aberrant †Author for correspondence immune responses, a well-defined regulatory B-cell subset may have the potential to be University College London, manipulated in vivo for the treatment of conditions such as rheumatoid arthritis, multiple Department of Medicine, 46 Cleveland Street, sclerosis, systemic lupus erythematosus and inflammatory bowel disease. In this review, we London W1T 4JF, UK discuss the latest findings showing that immature transitional-2 (T2-MZP) B cells can produce Tel.: +44 207 679 9679; IL-10 and are able to prevent or ameliorate collagen-induced arthritis. These results ascribe Fax: +44 207 679 9143; T2-MZP B cells with a previously unrecognized regulatory capacity. [email protected] In 1996, Charles Janeway demonstrated that, in vivo and in vitro) following B-cell depletion unlike wild-type controls, B-cell-deficient (μMT) [13,14]. Finally, IL-10-producing host B cells are mice, following immunization with the NH-ter- thought to be important in the protection of minal myelin basic protein encephalitogenic pep- transplant recipients from graft versus host dis- tide Ac1–11, failed to recover from experimental ease [15]. Recent reviews by Mauri [16] and autoimmune encephalomyelitis (EAE) [1]. This Mizoguchi cover these grounds extensively [17]. finding suggested that in a normal B-cell-suffi- Until recently there was no general consensus cient mouse, B cells, or a particular subset of B describing a unifying phenotype, mechanism of cells, could play an active role in controlling aber- protection or physiological location that would rant immune responses. Janeway et al. further suggest that immunoregulation observed in the hypothesized that these B cells, by virtue of their above models could be ascribed to a single B-cell ability to present antigens, might be necessary for subset. However, we have now described a subset maintaining Th2 responses in diseases that are of immature transitional B cells, transitional-2 predominantly mediated by the production of marginal-zone precursors (T2-MZPs), that pos- Th1 cytokines. It was not until the early 2000s sesses regulatory capacity in the CIA model of that more direct immunoregulatory mechanisms RA [18]. This subset of B cells reconciles several for this protection, including B-cell production of the features described in the different experi- of IL-10 and the induction of CD4+CD25+ mental models, and may be the likely candidate regulatory T cells (Tregs), were revealed [2,3]. for regulatory B cells (Bregs). In the past 10 years, B cells with a regulatory activity have been identified in a number of Adoptive transfer of T2-MZP Bregs prevents other immunological disorders. In models of or ameliorates arthritis autoimmunity, B cells have been shown to be The term ‘transitional B cell’ was coined by Car- protective against disease progression in both setti and colleagues to describe immature B cells Th1 (Gαi2-/-) and Th2 (TCRα-/-) models of that are phenotypically and functionally in tran- intestinal inflammation, and in the collagen- sition between the early immature B cells in the induced arthritis (CIA) model of rheumatoid bone marrow and mature B cells in the periphery arthritis (RA). They can also prevent non-obese [19]. Transitional B cells have been further subdi- diabetic mice from developing diabetes [4–10]. vided into subsets that reflect discrete matura- In studies of parasitic infections, B cells have tion stages in the periphery [20–24]. The exact been implicated in the inhibition of CD4+ number and phenotype of these subsets is still T-cell-mediated granuloma formation follow- controversial, but there is a growing consensus ing Schistosoma mansoni worm plus egg infec- dividing transitional B cells into transitional-1 Keywords: autoimmunity, tion, and in the resistance of mice to systemic (T1) B cells (whose precursors are the earliest B cell, regulatory, transitional-2 anaphylaxis following S. mansoni worm infec- IgM-positive immature B cells emigrating from tion [11,12]. Studies of B cells in cancer have the bone marrow), T2 B cells (derived from T1 part of shown enhanced antitumor immunity and nat- B cells), and a further intermediate subset ural killer T-cell and CD8+ T-cell activity (both between T2 B cells and mature MZ B cells, 10.2217/17460816.3.1.79 © 2008 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2008) 3(1), 79–84 79 REVIEW – Blair, Ehrenstein & Mauri T2-MZP B cells [21]. In this model, proposed arthritis [18]. It is not yet clear whether each originally by Allman et al., mature follicular T2-MZP B cell has the potential to be regula- (FO) B cells derive mainly from T2 B cells, while tory in addition to its role as an MZ B-cell pre- MZ B cells arise mainly from T2-MZP B cells cursor, or whether there is a functionally [25,26]. In the mouse, these B-cell subsets can be distinct, but phenotypically identical (in terms distinguished by their expression of some, or all, of the above markers), Breg subset [18]. There- of the markers IgM, IgD, CD1d, CD21, CD23, fore, we could argue that undergoing arthritis, CD24 and CD93, with T2-MZP identified as and the resolution of inflammation that fol- CD19+IgMhiIgDhiCD1dhiCD21hiCD23hiCD93+ lows, might either enrich the T2-MZP pool for B cells [25,27–29]. T2-MZP Bregs, or that antigenic stimulation We originally reported that adoptive transfer is required to enhance the suppressive activity of anti-CD40-treated splenic B cells to synge- of all T2-MZP B cells (i.e., by increasing the neic DBA mice could protect recipient mice production of IL-10 per cell) (Figure 1). from developing arthritis in the CIA model of Another important issue concerns the fate of RA [8]. This protection appeared to be mediated the transferred T2-MZP Bregs during the by the release of the immunoregulatory cytokine course of arthritis. While it is relatively well IL-10 by the transferred B cells. A follow-up established that T2-MZP B cells transferred to study of these ‘IL-10-producing Bregs’ revealed immune-deficient mice differentiate into that they were phenotypically indistinguishable mature MZ B cells, there are virtually no data from the previously identified T2-MZP B cells relating to the fate of transferred T2-MZP B [18]. Indeed, most IL-10+ B cells isolated from cells and, more importantly, those with regula- naive, as well as from immunized, mice tory function, in mice developing autoimmune expressed identical levels of IgM, IgD, CD1d, disease [26]. It has previously been shown that CD21, CD23, CD24 and CD93 to those MZ B cells produce high levels of IL-10; there- expressed by ‘conventional’ T2-MZP B cells [18]. fore, it would be feasible to hypothesize that Moreover, these IL-10-producing Bregs, isolated transferred T2-MZP B cells protect only after from naive mice, or mice in the remission phase differentiating into mature MZ B cells [9]. of arthritis, expressed Hes1 and Deltex1, the However, in the CIA model, transfer of MZ immediate downstream targets of the Notch-2 B cells not only failed to protect mice from signaling activity that is required for T2-MZP developing arthritis, but appeared to exacerbate and MZ development and survival, supporting the disease. their classification as T2-MZP B cells [30,31]. Adoptive transfer of T2-MZP B cells isolated Could Bregs from other models also be from the spleens of DBA/1 mice in the remission T2-MZP B cells? phase of arthritis significantly reduced the inci- In the autoimmune models described above, dence and the severity of disease in syngeneic Bregs were isolated from the spleen (EAE, recipient mice. By contrast, mice that received Gαi2-/- and TCRα-/- colitis) and mesenteric FO or MZ B cells or PBS developed a severe lymph nodes (TCRα-/- and Gαi2-/- colitis) [2,4,5]. arthritis. T2-MZP B cells also had a therapeutic However, T2-MZP B cells have so far been effect if transferred at the time of disease onset. described exclusively in the spleen [20]. There- From an immunological perspective, the protec- fore, those Bregs isolated from the mesenteric tion observed following transfer of T2-MZP B lymph nodes are unlikely to be conventional T2- cells was accompanied by the inhibition of CD4+ MZP B cells. Nevertheless, there are similarities T-cell proliferation and dampening of inflam- between T2-MZP B cells and Bregs in other matory Th1 responses [18]. autoimmune models. For example, like T2- Protection from arthritis was also seen when MZP Bregs, Bregs in the TCRα-/- colitis model the T2-MZP B cells were isolated from naive express high levels of CD1d [5], while Bregs iso- mice. To achieve the same degree of protection lated in CIA and EAE share a requirement for as observed following transfer of ‘remission’ CD40 [2,8]. Moreover, the spontaneous disease in T2-MZP B cells, twice as many naive T2-MZP the Gαi2-/- colitis model is associated with a B cells had to be transferred. Interestingly, decrease in the absolute numbers of T2-MZP B mice in remission from CIA have increased cells in this strain, suggesting a potential regula- numbers of IL-10-producing T2-MZP B cells tory role for T2-MZP in this model, although compared with mice before or during acute this has not yet been formally proven [4].
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