B cells and professional APCs recruit regulatory T cells via CCL4

Bystry, Richard S.; Aluvihare, Varuna; Welch, Keasley; Kallikourdis, Marinos; Betz, Alexander G.

doi:10.1038/ni735

Cited by 462 publications

(370 citation statements)

References 31 publications

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“…Bystry et al previously demonstrated that CD4 ϩ CD25 ϩ T cells inhibited LPS-mediated B-cell proliferation. 37 Lim et al also recently demonstrated that regulatory T cells can suppress B-celldependent immunoglobulin production and class switch recombination in the absence of T-helper cells. 38 However, the mechanism for the suppression remains unclear in these studies.…”

Section: Discussionmentioning

confidence: 99%

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Zhao

Thornton

DiPaolo

et al. 2006

Blood

426

337

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IntroductionCD4 ϩ CD25 ϩ regulatory/suppressor T cells were originally identified by their capacity to primarily control immune responses to autoantigens, 1-3 but recent studies have shown that they exert pleiotropic suppressive effects on immune responses to alloantigens, 4 tumor antigens, 5 and infectious agents. 6,7 The functional phenotype of CD4 ϩ CD25 ϩ T cells has been extensively characterized in vitro. CD4 ϩ CD25 ϩ T cells do not proliferate when stimulated via the TCR but are able to proliferate when costimulated with IL-2. 8,9 On activation via their TCR, they suppress the proliferation of both CD4 ϩ T cells 8 and CD8 ϩ T cells 10 by inhibiting the transcription of IL-2 mRNA. 8 In vitro studies have demonstrated that the suppression is mediated exclusively by a cell-contact-dependent, cytokine-independent mechanism. 4,9,10 However, suppression in some in vivo experimental models requires the cooperation of suppressive cytokines. [11][12][13] The nature of the target cells for CD4 ϩ CD25 ϩ T-cell-mediated suppression remains controversial. CD4 ϩ CD25 ϩ T cells can suppress the activation of CD8 ϩ T cells in the absence of professional antigenpresenting cells (APCs), 10 but this does not exclude the possibility that they are also capable of acting on other cell types. One recent study has suggested that some (or all) of the suppressive effects of mouse CD4 ϩ CD25 ϩ T cells on T-cell proliferation are secondary to CD4 ϩ CD25 ϩ T-cell-mediated killing of the responder cells by a perforin-independent, granzyme-B-dependent pathway. 14 In the day 3 thymectomy model of organ-specific autoimmune disease, CD4 ϩ CD25 ϩ T cells suppressed the activation of autoantigenspecific T cells and inhibited the production of autoantibodies to the target organ. 2,3 Similar results have been obtained in cell transfer studies using TCR transgenic T cells. [15][16][17][18] However, it remains unclear whether these results are secondary to a direct effect of CD4 ϩ CD25 ϩ T cells on B-cell function or whether the effects are mediated indirectly by an inhibition of T-helper function. One recent study has shown that activation of both human T regulatory 1 (Tr1)-like cells and CD4 ϩ CD25 ϩ T cells by cross-linking CD3 and CD46 induces potent lytic activity against T cells, monocytes, and dendritic cells. 19 In this study, we examined the effects of CD4 ϩ CD25 ϩ T cells on B-cell function. We demonstrate that CD4 ϩ CD25 ϩ T cells suppress B-cell proliferation in response to polyclonal B-cell activators by inducing death of the responding B cells. Most interestingly, B-cell death is not mediated by the Fas-Fas ligand (FasL) pathway, but instead is mediated by a granzyme-dependent, partially perforin-dependent pathway. The implications of these findings for the role of CD4 ϩ CD25 ϩ T cells in the control of B-cell function in vivo are discussed. Materials and methods MiceFemale BALB/c and C57BL/6 mice were obtained from the National Cancer Institute (Frederick, MD). Mice expressing a transgenic TCR specific for influenza hemagglutinin...

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Section: Discussionmentioning

confidence: 99%

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Zhao

Thornton

DiPaolo

et al. 2006

Blood

426

337

View full text Add to dashboard Cite

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“…Rather than representing a Th2-selective cytokine, IL-10 is produced by different subsets of regulatory T cells, including the peripherally derived Tr1 cells (56). Indeed, an important role for regulatory T cells within GCs was described recently in the mouse where these T cells were shown to be selectively recruited/retained within the follicles by their expression of CCR5 (57). Because IL-10-producing T cells with regulatory function also can be anergic (58), the human CD57 ϩ GC T cells may be analogous to these murine CCR5 ϩ GC T cells.…”

Section: Discussionmentioning

confidence: 99%

Germinal Centers Regulate Human Th2 Development

Johansson‐Lindbom

Ingvarsson

Borrebaeck

2003

The Journal of Immunology

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In the present study we demonstrate that all CD4+ T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-γ, after in vitro activation. CD4+ T cells, which express only intermediate levels of CXCR5, instead develop into IFN-γ-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2+ Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57+ GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.

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“…Although there is now ample evidence that Tregs can regulate T cell-mediated responses, their role on the humoral response has been less explored. In a recent study (52), it was shown that a depletion or a lack of recruitment of Tregs to B cells and APCs resulted in a deregulated humoral response. A direct role of Tregs on B cells was evidenced in the same study because the authors further showed that Tregs can suppress LPS-induced B cell activation.…”

Section: Discussionmentioning

confidence: 99%

Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus

Miyara

Amoura

Parizot

et al. 2005

The Journal of Immunology

413

319

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The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57 ± 0.24%, n = 45 vs 1.29 ± 0.38%, n = 82, p < 0.0001) or with inactive patients (1.22 ± 0.67%, n = 62, p < 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls’ values (1.15 ± 0.46%, n = 21, p = 0.09 and 1.16 ± 0.44%, n = 16, p = 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.

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B cells and professional APCs recruit regulatory T cells via CCL4

Cited by 462 publications

References 31 publications

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Activated CD4+CD25+ T cells selectively kill B lymphocytes

Germinal Centers Regulate Human Th2 Development

Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus

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