Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis
Vissia Viglietta, Clare Baecher-Allan, Howard L Weiner, David A Hafler, Vissia Viglietta, Clare Baecher-Allan, Howard L Weiner, David A Hafler
Abstract
CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.
Figures
References
- Ota, K., M. Matsui, E.L. Milford, G.A. Mackin, H.L. Weiner, and D.A. Hafler. 1990. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 346:183–187.
- Kappler, J.W., N. Roehm, and P. Marrack. 1987. T cell tolerance by clonal elimination in the thymus. Cell. 49:273–280.
- Sakaguchi, S. 2000. Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 101:455–458.
- Shevach, E.M., R.S. McHugh, C.A. Piccirillo, and A.M. Thornton. 2001. Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol. Rev. 182:58–67.
- Sakaguchi, S., K. Fukuma, K. Kuribayashi, and T. Masuda. 1985. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161:72–87.
- Read, S., V. Malmstrom, and F. Powrie. 2000. Cytotoxic T lymphocyte–associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192:295–302.
- Suri-Payer, E., A.Z. Amar, A.M. Thornton, and E.M. Shevach. 1998. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 160:1212–1218.
- Salomon, B., D.J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, and J.A. Bluestone. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+ CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 12:431–440.
- Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M. Toda. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151–1164.
- Powrie, F., S. Mauze, and R.L. Coffman. 1997. CD4+ T-cells in the regulation of inflammatory responses in the intestine. Res. Immunol. 148:576–581.
- Baecher-Allan, C., J.A. Brown, G.J. Freeman, and D.A. Hafler. 2001. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167:1245–1253.
- Stephens, L.A., C. Mottet, D. Mason, and F. Powrie. 2001. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur. J. Immunol. 31:1247–1254.
- Dieckmann, D., H. Plottner, S. Berchtold, T. Berger, and G. Schuler. 2001. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J. Exp. Med. 193:1303–1310.
- Thornton, A.M., and E.M. Shevach. 1998. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188:287–296.
- Shevach, E.M. 2000. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18:423–449.
- Martin, R., B. Gran, Y. Zhao, S. Markovic-Plese, B. Bielekova, A. Marques, M.H. Sung, B. Hemmer, R. Simon, H.F. McFarland, and C. Pinilla. 2001. Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease. J. Autoimmun. 16:187–192.
- O'Connor, K.C., A. Bar-Or, and D.A. Hafler. 2001. The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J. Clin. Immunol. 21:81–92.
- Steinman, L., R. Martin, C. Bernard, P. Conlon, and J.R. Oksenberg. 2002. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25:491–505.
- Scholz, C., K.T. Patton, D.E. Anderson, G.J. Freeman, and D.A. Hafler. 1998. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J. Immunol. 160:1532–1538.
- Viglietta, V., S.C. Kent, T. Orban, and D.A. Hafler. 2002. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J. Clin. Invest. 109:895–903.
- Lovett-Racke, A.E., J.L. Trotter, J. Lauber, P.J. Perrin, C.H. June, and M.K. Racke. 1998. Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells. J. Clin. Invest. 101:725–730.
- Reijonen, H., E.J. Novak, S. Kochik, A. Heninger, A.W. Liu, W.W. Kwok, and G.T. Nepom. 2002. Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes. 51:1375–1382.
- Levings, M.K., R. Sangregorio, and M.G. Roncarolo. 2001. Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J. Exp. Med. 193:1295–1302.
- Baecher-Allan, C., V. Viglietta, and D.A. Hafler. 2002. Inhibition of human CD4(+)CD25(high) regulatory T cell function. J. Immunol. 169:6210–6217.
- Pasare, C., and R. Medzhitov. 2003. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 299:1033–1036.
- Kohm, A.P., P.A. Carpentier, H.A. Anger, and S.D. Miller. 2002. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169:4712–4716.
- Szanya, V., J. Ermann, C. Taylor, C. Holness, and C.G. Fathman. 2002. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J. Immunol. 169:2461–2465.
- Kohm, A.P., and S.D. Miller. 2003. Role of ICAM-1 and P-selectin expression in the development and effector function of CD4+CD25+regulatory T cells. J. Autoimmun. 21:261–271.
Source: PubMed