SEARCH:   Advanced

Blood, 1 June 2006, Vol. 107, No. 11, pp. 4203-4204. 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 Waller, E. K. Search for Related Content PubMed Articles by Waller, E. K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Noble et al, page 4475 A tale of two T cells: suppressor CD8 T cells recalled to life Edmund K. Waller WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY The paper by Noble and colleagues describes a novel population of regulatory CD8+ T cells that is generated in vitro by exposure of CD8+ T cells to the combination of IL-4 and IL-12. In the 1970s, 2 types of CD8+ T cells were described: cytotoxic and suppressor, with the suppressor population found in the blood of patients who underwent allogeneic bone marrow transplantation (BMT) and Hodgkin lymphoma patients treated with total lymphoid irradiation.1,2 Suppressor T cells inhibited lectin-induced T-cell proliferation and B-cell immunoglobulin synthesis and T-cell proliferation in mixed lymphocyte reactions.3 Suppressor T cells were hypothesized to be responsible for the clinical immunosuppression observed among these patients,4 but their precise identity, distinction from effector CD8+ T cells, and mechanism of action were unclear. Interest in suppressor CD8+ T cells waned during the decades in which antigen-specific cytotoxic CD8+ T-cell responses were defined and antigen presentation by dendritic cells was discovered. Data presented by Noble and colleagues in this issue of Blood shed new light on these interesting regulatory cells. The authors found that CD8+ Tregs inhibited the generation of Th1/Tc1 and Th2/Tc1 antigen-specific effector responses. The cytokine profile of the CD8+ Tregs was similar to that of their CD4+ counterparts, with synthesis and secretion of high levels of IL-10 and IFN-, but the former cells are augmented by the presence of glucocorticoids, while CD4+ Tregs were not. The presence of a phenotypically similar population following in vivo immunization suggests that this phenomenon is part of the physiologic regulation of immune responses. The data presented by the authors use OT-1 and OT-2 transgenic T cells to track antigen-specific immune responses in vivo as well as a parenteral F1 graft-versus-host disease (GVHD) model to demonstrate physiologic relevance of the CD8 Tregs to regulating immune responses. Inhibition of antigen-specific effector immune responses required relatively high ratios of CD8+ Tregs to effectors with cell-to-cell contact, and was not blocked by neutralizing secreted IL-10 or TGF-, or the presence of a Golgi poison to block cytokine secretion, but could be reversed by anti-CD28 antibodies. These new data indicate that the regulation of immune responses is redundant, with multiple stimulatory and inhibitory pathways that converge on the same intermediates and effector cell populations. The addition of CD8+ Tregs to the regulatory dendritic cells that are generated by TGF-, IL-10, or VIP5 adds another important counterregulatory system that limits immune responses. The map of these connections begins to look like a New York City subway map, with overlapping routes delivering counterbalancing activation and inhibitory signals (see figure). View larger version (66K): [in this window] [in a new window]   Pathways of immune regulation. Positive signals for immune activation are shown as green arrows; inhibitory signals are shown as red lines terminating in red bars. Blue arrows represent differentiation pathways and/or secreted cytokines. Generation of CD8+ Tregs occurs under the influence of IL-12 made by Th1 and IL-4 made by Th2 T cells.   The paper by Noble et al generates many questions regarding the role of Tregs in regulating normal adaptive and pathologic immune responses. Does the generation of Tregs depend upon the initial generation of antigen-specific CD4+ T cells that release IL-4 and IL-12 into the local microenvironment? Do IL-4 or IL-12 knock-out mice have fewer CD8 Tregs in vivo and a greater propensity for dysregulated cellular immune responses, or does the redundancy of the proposed model limit the phenotype of a deficit in any single pathway? Is the toxicity of the anti-CD28 antibody recently tested in a phase 1 clinical trial due to a reversal of the inhibitory activity of Tregs? The emerging picture of immune regulation is ever more exciting in this "best of times" for immunology. References Tsoi MS, Storb R, Dobbs S, et al. NonspecifIc suppressor cells in patients with chronic graft-vs-host disease after marrow grafting. J Immunol. 1979;123: 1970-1976.[Abstract/Free Full Text] Posner MR, Reinherz E, Lane H, Mauch P, Hellman S, Schlossman SF. Circulating lymphocyte populations in Hodgkin's disease after mantle and paraaortic irradiation. Blood. 1982;61: 705-708. Abdou NL, Alavi JB, Nabih I, Abdou, NI. Human bone marrow lymphocytes: B and T cell precursors and subpopulations. Blood. 1976;47: 423-430.[Abstract/Free Full Text] Velardi A, Terenzi T, Cucciaioni S, et al. Imbalances within the peripheral blood T-helper (CD4+) T-suppressor (CD8+) cell populations in the reconstitution phase after human bone marrow transplantation. Blood. 1988;71: 1196-1200.[Abstract/Free Full Text] Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory dendritic cells that can prevent acute graft-versus-host disease while maintaining graft-versus-tumor. Blood. Prepublished on January 17, 2006, as DOI 10.1182/blood-2005-11-4495.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Cytokine-induced IL-10–secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage Alistair Noble, Angela Giorgini, and Jamie A. Leggat Blood 2006 107: 4475-4483. [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 Waller, E. K. Search for Related Content PubMed Articles by Waller, E. K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020