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Blood, 15 May 2006, Vol. 107, No. 10, pp. 3818-3819. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Campbell, J. J. Search for Related Content PubMed Articles by Campbell, J. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Zhao et al, page 3925 Tregs control B-cell life and death James J. Campbell HARVARD MEDICAL SCHOOL In this issue, Zhao and colleagues describe the surprising finding that CD4+CD25+ regulatory T cells (Tregs) abrogate B-cell proliferation by direct induction of B-cell death through granzyme- and perforin-dependent pathways. Regulatory T cells have received much attention in recent years for their ability to dampen otherwise severe immune responses. Understanding the mechanisms by which such cells control immune responses could lead to innovative clinical interventions: The ability to increase specific regulatory T-cell (Treg) activities could potentially control a variety of autoimmune diseases. Further, inhibition of specific Treg activities could break immunotolerance to cancer cells, allowing normal immune responses to eliminate tumors. It has been clear since 2001 that activated CD4+CD25+ T cells could inhibit proliferation and Ig secretion of LPS-activated B cells, but the mechanisms of action remained unclear. Zhao and colleagues have found that activated T cells are able to inhibit B-cell proliferation by directly inducing apoptosis of the proliferating B cells themselves. This mechanism is quite different from how Tregs control T-cell proliferation, in which Tregs prevent IL-2 production by proliferating T cells. The authors demonstrate convincingly that CD4+CD25+ T cells do not induce B-cell apoptosis through the pathways that would normally be associated with lymphocyte-lymphocyte interactions (ie, Fas/FasL, TNF/TNFR, or TRAIL/TRAILR). Instead, the apoptotic event requires a combination of granzyme B and perforin activities. The requirement for these 2 pathways is reminiscent of the manner in which CD8 cytotoxic T cells kill their targets through class I–dependent antigen recognition. In fact, the authors demonstrate that activated CD4+CD25+ T cells produce and release granzyme B similarly to CD8 T cells, an activity not found in CD4+CD25– T cells. The authors further demonstrate that B-cell apoptosis mediated by CD4+CD25+ T cells can be antigen dependent. CD4+CD25+ T cells from mice bearing a transgenic TCR that recognizes an ovalbumin peptide were used for these experiments. Proliferating B cells were divided into 2 separate groups, one pulsed with ovalbumin and one unpulsed. Ovalbumin-specific CD4+CD25+ T cells were dramatically more efficient at killing antigen-pulsed B cells, demonstrating that this Treg activity is indeed antigen dependent. Thus, an entirely new mechanism of Treg activity has been discovered. B-cell proliferation is controlled in a completely different manner from T-cell proliferation. This mechanism involves direct, antigen-selective induction of B-cell apoptosis. These findings are an important advance in our knowledge of Treg function. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Activated CD4+CD25+ T cells selectively kill B lymphocytes Dong-Mei Zhao, Angela M. Thornton, Richard J. DiPaolo, and Ethan M. Shevach Blood 2006 107: 3925-3932. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Campbell, J. J. Search for Related Content PubMed Articles by Campbell, J. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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