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CD8+ T suppressor cells are back to the game: are they players in autoimmunity?
Autoimmunity Reviews 1 (2002) 279–283
CD8q T suppressor cells are back to the game: are they players in autoimmunity? Gilberto Filacia,*, Nicole Suciu-Focab a
Department of Internal Medicine, University of Genoa, Viale Benedetto XV n.6, 16132-Genova, and Center of Excellence for Biomedical Research, Genova, Italy b Columbia University, Department of Pathology, New York, NY 10032, USA Received 7 June 2002; accepted 28 June 2002
Abstract The CD8q T suppressor lymphocytes identified in humans belong to three different subpopulations. All of them inhibit the proliferation of antigen-specific T cells. The type 1 and type 2 of CD8q T suppressor cells are characterized by the CD8qCD28y phenotype, while no detailed data are available at the moment on the phenotype of the type 3 of CD8q T suppressor cells. The type 1 of CD8q suppressor T lymphocytes acts by inducing alteration of expression of co-stimulatory molecules on dendritic cells. A cell-to-cell contact is required to mediate this effect. The type 2 of CD8q T suppressor cells induces inhibition via cytokine secretion (IFNg, IL6) and do not need to interact directly with antigen presenting cells. The type 3 of CD8q T suppressor cells mediates its function through the secretion of IL10. The complexity and multiplicity of CD8q T suppressor cell subsets suggests that these cells may have an important role in the regulation of the immune homeostasis, acting together with the CD4q T regulatory cell subpopulations. The specificity of the functions of each of these suppressory regulatory subsets in the immune network requires to be clarified to better understand the immune system, its functions and the possibilities to modulate its activities in the course of immune-mediated diseases. 䊚 2002 Elsevier Science B.V. All rights reserved. Keywords: CD8q T suppressor cells; Immune regulation; Immune tolerance
1. Introduction The major enigma of immunology concerns mechanism(s) inducing the phenomenon of the selfynon-self recognition and discrimination. This topic has become even more intriguing, in the last *Corresponding author. Tel.: q39-010-3538984; fax: q39010-3538994. E-mail address: [email protected] (G. Filaci).
10–15 years, because of the finding that both B and T lymphocytes specific for endogenous antigens escape central deletion and localize in the periphery of healthy individuals. This implies that such autoreactive cells must be strictly controlled by peripheral tolerogenic mechanisms to avoid the onset of autoimmune reactions. Indeed, regulatory cells belonging to different cell lineages have been identified. Among them are the CD4qCD25q T
1568-9972/02/$ - see front matter 䊚 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 8 - 9 9 7 2 Ž 0 2 . 0 0 0 6 5 - 4
280
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
cells, which play a central role as demonstrated by their capacity to control experimental autoimmune diseases w1,2x. Other regulatory T cells are elicited in response to antigens presented by immature dendritic cells (DC) or by a particular subtype defined as DC2 w3,4x. Under particular condition, i.e. after phagocytosis of apoptotic bodies, macrophages can also induce immune suppression acting via paracrine mechanisms on neighboring DC (personal unpublished observation). The cells that were first suspected to have an immunosuppressive function are the CD8q T lymphocytes, as proposed by Gershon and Kondo w5x. Subsequent studies, however, have been unable to confirm their results. Over the last ten years the concept that CD8q T cells with suppressor function regulate the immune response has re-emerged. Antigen-specific CD8q T suppressor (Ts) lymphocytes have been isolated from mice and humans w6–8x and evidence has been provided that they suppress autoimmune responses in mice with experimental autoimmune encephalomielitis w9x. 2. Phenotype Phenotypically, CD8q Ts cells are characterized by the lack of expression of the CD28 molecule w6,10,11x. More specific markers of these cells andyor of their precursors have not been published yet. It appears, however, that the type 2 subset of CD8q Ts cells (see below) possesses a naive phenotype (CD45RAq, CD45Roy, CD62Lhigh) (Filaci et al., in preparation). This finding is consistent with the fact that this particular cell subset does not require recognition of antigens presented by antigen presenting cells (APC) to exhibit its suppressor activity (personal observations). No data are available on the phenotype of other subpopulations of CD8q Ts cells. 3. CD8H T suppressor cells: type 1 In humans three different subsets of CD8q Ts cells have been functionally identified. One of these subsets, actively studied by Suciu-Foca et al., is represented by CD8qCD28y T cells which inhibit allo-antigen, xeno-antigen and nominal antigen-specific CD4q T cell responses w10,12,13x.
CD8qCD28y Ts cells were generated in vitro by multiple rounds of stimulation of peripheral blood mononuclear cell with allogeneic, xenogeneic or antigen-pulsed syngeneic APC w10,12x. Ts were shown to recognize MHC class I antigens on stimulating APC inhibiting their capacity to elicit the proliferation of antigen-specific CD4q T helper cells. In the presence of Ts, T helper cells become anergic showing impaired capacity to secrete IL2 and express CD40L w10,12–15x. To mediate their effects these CD8q Ts cells need to interact (recognizing the specific antigen in the MHC class I context) with dendritic cells. The consequence of this interaction is the inhibition of the CD40mediated up-regulation of other co-stimulatory molecules (CD80 and CD86) and the upregulation of expression of the immunoglobulin-like transcript ILT3 and ILT4 on the surface of dendritic cells w16x. In this system the dendritic cell behaves as a bridge between the CD8q Ts and the antigenspecific CD4q T helper cells. The impairment of antigen presenting cell function of the dendritic cell, caused by the effects of the CD8q Ts lymphocyte, prevents the proliferation of the CD4q T helper cell. Evidence has been provided that the presence of CD8qCD28y Ts cells capable to inhibit CD40-triggering and to induce the upregulation of ILT3 and ILT4 on donor APC correlates positively with the absence of acute rejection episodes in transplanted patients w16,17x. 4. CD8H T suppressor cells: type 2 Another type of CD8q Ts cells was generated in vitro from purified circulating CD8q lymphocytes incubated for 1 week with monocytes, IL2 and GM-CSF. Ts cells inhibited the proliferative response of T cells stimulated with specific antigens, anti-CD3 monoclonal antibodies or mitogens w18x. Furthermore, they also seem to suppress the lysis mediated by cytotoxic cells (Filaci et al., unpublished). The mechanism of action of this subset of CD8q suppressor cell is not yet completely understood, although it is clear that they exert their function through soluble factors without direct interaction with APC. Thus, when separated
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
281
Fig. 1. Schematic representation of the three subpopulations of CD8q T suppressor cells identified in humans. Upper row: The type 1 of CD8q T suppressor cells recognize the HLA class I-antigen complex on dendritic cells and induce down-modulation of costimulatory functions. Middle row: The type 2 of CD8q T suppressor cells are generated by incubation with IL2 and GM-CSF and induce inhibition of CD4q T cell proliferation through secretion of IFNg and IL6. Lower row: The type 3 of CD8q T suppressor ¨ CD8q T cells via secretion of IL10. cells are generated after interaction with (plasmocytoid) DC2 and induce inhibition of naıve
282
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
from the stimulated T cells by a pored membrane, which prevents direct cell-to-cell contact while allowing the passage of cytokines, their suppressor activity is not halted. Studies of intracellular cytokines revealed the presence of IFNg, IL6 and IL12. Using an anti-IFNg blocking antibody or oligonucletides antisense for the sequence of IL6 mRNA we could antagonize the suppressor function of these cells. Thus, IFNg and IL6 (directly or through the induction of others cytokines) are involved in the inhibition of T cell proliferation mediated by this subset of CD8q T suppressor cell w11x. Our still unpublished data suggest that generation of these cells does not require MHC recognition. Thus, it is possible to generate CD8q T suppressor cells using allogeneic monocytes from an HLA class I unmatched donor. It is unclear which lymphocyte subpopulation contains the circulating precursors of these cells. Healthy subjects have CD8qCD28q and CD8qCD28y T cell subpopulations almost equally distributed in the peripheral blood. The CD8q T suppressor cells, that are CD28y, could derive from the former subpopulation, via the down-regulation of the CD28 molecule, or from the latter subset, that is already CD28y. Recent evidences suggest that when CD8qCD28q cells are separated from CD8qCD28y cells, generation of suppressor cells was possible only from the latter but not from the former cell subset. This suggests that the noncommitted circulating CD8qCD28y cells represent the source for generation of suppressor cells in tissue sites of inflammation andyor in lymph nodes (Filaci et al., unpublished). Preliminary studies suggest that the percentage of CD8qCD28y cells decreases in patients with systemic autoimmune diseases (SLE and systemic sclerosis) during relapses. It is therefore possible that during phases of disease reactivation the CD8qCD28y pool of T cells is depleted of suppressor cells andyor that CD8qCD28y suppressor T cells home into tissues and lymph nodes leaving the circulation (Filaci et al., unpublished). Future studies may elucidate the reason why impairment of CD8q Ts generation occurs in patients affected by SLE and multiple sclerosis during relapses w11,18x. Attempts to generate CD8q T suppressor cells from patients with active SLE have failed,
resulting in the expansion of T cells that showed no inhibitory activity and secreted reduced IL6 and increased IL12 amounts. 5. CD8H T suppressor cells: type 3 A third subpopulation of CD8q suppressor lymphocytes has been recently identified w19x. These cells were generated by stimulating purified, naive CD8q T lymphocytes with plasmacytoid dendritic cells (DC2). Their generation depends on antigen presentation and secretion of IL10 by DC2. DC2primed T cells develop energy to further stimulation with the same antigen and start secreting IL10 ¨ themselves. Their inhibitory activity affects naıve but not preactivated CD8q T cells and is directly mediated by IL10. The phenotype of these cells and their clinical relevance have not been analyzed (Fig. 1). 6. Conclusions Data obtained in the last 10 years demonstrate that immune homeostasis is controlled by several regulatory T cell subsets. Functional alterations of these cells may be associated with the onset of autoimmune phenomena. These findings are adding clues to our understanding of the pathogenesis of autoimmune diseases, which may result from an impaired balance between effector and regulatory cells. Study of immunoregulatory mechanisms may be crucial to the development of new strategies for treatment of autoimmune disorders. 7. Summary In recent years three different CD8q T suppressor cell subpopulations have been identified and functionally characterized in humans. Each of these suppressor subsets act in different ways to regulate antigen-specific T cell responses. Functional alterations were shown to be associated with the relapse of autoimmune diseases and onset of acute rejection episodes in transplanted recipients. A better understanding of immunoregulatory mechanisms is crucial to treatment of autoimmune diseases.
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
Acknowledgments This study has been supported by grants from Ministero della Sanita’-Istituto Superiore di Sanita’, programma nazionale di ricerche sull’AIDS 1999 (n. 30C.39), and by MURST National Program ‘Meccanismi umorali e cellulari di modulazione dell’immunoflogosi’ (n. 9706117821-001). Take-home messages ● Three CD8q T suppressor cell (CD8q Ts) populations, inhibiting the proliferative activity of antigen-specific T lymphocytes, have been identified in humans. ● The types 1 and 2 of CD8q Ts are phenotypically characterized to be CD8qCD28y cells. ● The type 1 acts by down-modulating the expression of co-stimulatory molecules on dendritic cells. ● The type 2 inhibits proliferation via cytokine secretion (IFNg and IL6). ● The type 3 function is IL10-dependent. ● Numerical andyor functional alterations of type 1 or type 2 of CD8q Ts have been demonstrated in patients rejecting transplanted organs or in patients suffering for relapses of autoimmune diseases such as SLE and MS, respectively.
References w1x Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of cd4(q)cd25(q) t cells with regulatory properties from human blood. J Exp Med 2001;193:1303 –10. w2x Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AK. Identification and functional characterization of human cd4(q)cd25(q) t cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285 –94. w3x Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245 –52. w4x Pulendran B, Maraskovsky E, Banchereau J, Maliszewski C. Trends Immunol 2001;22:41 –7. w5x Gershon RK, Kondo K. Infectious immunological tolerance. Immunology 1971;21:903 –13.
283
w6x Damle NK, Engleman EG. Antigen-specific suppressor T lymphocytes in man. Clin Immunol Immunopathol 1989;53:S17 –S24. w7x Sercarz E, Krzych U. The distinctive specificity of antigen-specific suppressor T cells. Immunol Today 1991;12:111 –8. w8x Yuen MH, Protti MP, Diethelm-Okita B, Moviola L, Howard JF, Conti-Fine BM. Immunoregulatory CD8q cells recognize antigen-activated CD4q cells in myasthenia gravis patients and in healthy controls. J Immunol 1995;154:1508 –20. w9x Sun D, Qin Y, Chluba J, Epplen JT, Wekerle H. Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T–T cell interactions. Nature 1988;332:843 –5. w10x Liu Z, Tugulea S, Cortesini R, Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8qCD28y T cells. Int Immunol 1998;10:775 –83. w11x Filaci G, Bacilieri S, Fravega M, et al. Impairment of CD8q T suppressor cell function in patients with active systemic lupus erythematosus. J Immunol 2001;166:6452 –7. w12x Ciubotariu R, Colovai AI, Pennesi G, et al. Specific suppression of human CD4q Th cell responses to pig MHC antigens by CD8qCD28y regulatory T cells. J Immunol 1998;161:5193 –202. w13x Jiang S, Tugulea S, Pennesi G, et al. Induction of MHCclass I restricted human suppressor T cells by peptide priming in vitro. Hum Immunol 1998;59:690 –9. w14x Colovai AI, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N. Induction of xenoreactive CD4q Tcell anergy by suppressor CD8qCD28y T cells. Transplantation 2000;69:1304 –10. w15x Liu Z, Tugulea S, Cortesini R, Lederman S, Suciu-Foca N. Inhibition of CD40 signaling pathway in antigen presenting cells by T suppressor cells. Hum Immunol 1999;60:568 –74. w16x Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by Ts cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 2002;3:237 –43. w17x Ciubotariu R, Vasilescu R, Ho E, et al. Detection of T suppressor cells in patients with organ allografts. Hum Immunol 2001;62:15 –20. w18x Balashov KE, Khoury SJ, Hafler DA, Weiner HL. Inhibition of T cell responses by activated human CD8q T cells is mediated by interferon-g and is defective in chronic progressive multiple sclerosis. J Clin Invest 1995;95:2711 –9. w19x Gilliet M, Liu Y-J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 2002;195:695 –704.
CD8q T suppressor cells are back to the game: are they players in autoimmunity? Gilberto Filacia,*, Nicole Suciu-Focab a
Department of Internal Medicine, University of Genoa, Viale Benedetto XV n.6, 16132-Genova, and Center of Excellence for Biomedical Research, Genova, Italy b Columbia University, Department of Pathology, New York, NY 10032, USA Received 7 June 2002; accepted 28 June 2002
Abstract The CD8q T suppressor lymphocytes identified in humans belong to three different subpopulations. All of them inhibit the proliferation of antigen-specific T cells. The type 1 and type 2 of CD8q T suppressor cells are characterized by the CD8qCD28y phenotype, while no detailed data are available at the moment on the phenotype of the type 3 of CD8q T suppressor cells. The type 1 of CD8q suppressor T lymphocytes acts by inducing alteration of expression of co-stimulatory molecules on dendritic cells. A cell-to-cell contact is required to mediate this effect. The type 2 of CD8q T suppressor cells induces inhibition via cytokine secretion (IFNg, IL6) and do not need to interact directly with antigen presenting cells. The type 3 of CD8q T suppressor cells mediates its function through the secretion of IL10. The complexity and multiplicity of CD8q T suppressor cell subsets suggests that these cells may have an important role in the regulation of the immune homeostasis, acting together with the CD4q T regulatory cell subpopulations. The specificity of the functions of each of these suppressory regulatory subsets in the immune network requires to be clarified to better understand the immune system, its functions and the possibilities to modulate its activities in the course of immune-mediated diseases. 䊚 2002 Elsevier Science B.V. All rights reserved. Keywords: CD8q T suppressor cells; Immune regulation; Immune tolerance
1. Introduction The major enigma of immunology concerns mechanism(s) inducing the phenomenon of the selfynon-self recognition and discrimination. This topic has become even more intriguing, in the last *Corresponding author. Tel.: q39-010-3538984; fax: q39010-3538994. E-mail address: [email protected] (G. Filaci).
10–15 years, because of the finding that both B and T lymphocytes specific for endogenous antigens escape central deletion and localize in the periphery of healthy individuals. This implies that such autoreactive cells must be strictly controlled by peripheral tolerogenic mechanisms to avoid the onset of autoimmune reactions. Indeed, regulatory cells belonging to different cell lineages have been identified. Among them are the CD4qCD25q T
1568-9972/02/$ - see front matter 䊚 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 8 - 9 9 7 2 Ž 0 2 . 0 0 0 6 5 - 4
280
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
cells, which play a central role as demonstrated by their capacity to control experimental autoimmune diseases w1,2x. Other regulatory T cells are elicited in response to antigens presented by immature dendritic cells (DC) or by a particular subtype defined as DC2 w3,4x. Under particular condition, i.e. after phagocytosis of apoptotic bodies, macrophages can also induce immune suppression acting via paracrine mechanisms on neighboring DC (personal unpublished observation). The cells that were first suspected to have an immunosuppressive function are the CD8q T lymphocytes, as proposed by Gershon and Kondo w5x. Subsequent studies, however, have been unable to confirm their results. Over the last ten years the concept that CD8q T cells with suppressor function regulate the immune response has re-emerged. Antigen-specific CD8q T suppressor (Ts) lymphocytes have been isolated from mice and humans w6–8x and evidence has been provided that they suppress autoimmune responses in mice with experimental autoimmune encephalomielitis w9x. 2. Phenotype Phenotypically, CD8q Ts cells are characterized by the lack of expression of the CD28 molecule w6,10,11x. More specific markers of these cells andyor of their precursors have not been published yet. It appears, however, that the type 2 subset of CD8q Ts cells (see below) possesses a naive phenotype (CD45RAq, CD45Roy, CD62Lhigh) (Filaci et al., in preparation). This finding is consistent with the fact that this particular cell subset does not require recognition of antigens presented by antigen presenting cells (APC) to exhibit its suppressor activity (personal observations). No data are available on the phenotype of other subpopulations of CD8q Ts cells. 3. CD8H T suppressor cells: type 1 In humans three different subsets of CD8q Ts cells have been functionally identified. One of these subsets, actively studied by Suciu-Foca et al., is represented by CD8qCD28y T cells which inhibit allo-antigen, xeno-antigen and nominal antigen-specific CD4q T cell responses w10,12,13x.
CD8qCD28y Ts cells were generated in vitro by multiple rounds of stimulation of peripheral blood mononuclear cell with allogeneic, xenogeneic or antigen-pulsed syngeneic APC w10,12x. Ts were shown to recognize MHC class I antigens on stimulating APC inhibiting their capacity to elicit the proliferation of antigen-specific CD4q T helper cells. In the presence of Ts, T helper cells become anergic showing impaired capacity to secrete IL2 and express CD40L w10,12–15x. To mediate their effects these CD8q Ts cells need to interact (recognizing the specific antigen in the MHC class I context) with dendritic cells. The consequence of this interaction is the inhibition of the CD40mediated up-regulation of other co-stimulatory molecules (CD80 and CD86) and the upregulation of expression of the immunoglobulin-like transcript ILT3 and ILT4 on the surface of dendritic cells w16x. In this system the dendritic cell behaves as a bridge between the CD8q Ts and the antigenspecific CD4q T helper cells. The impairment of antigen presenting cell function of the dendritic cell, caused by the effects of the CD8q Ts lymphocyte, prevents the proliferation of the CD4q T helper cell. Evidence has been provided that the presence of CD8qCD28y Ts cells capable to inhibit CD40-triggering and to induce the upregulation of ILT3 and ILT4 on donor APC correlates positively with the absence of acute rejection episodes in transplanted patients w16,17x. 4. CD8H T suppressor cells: type 2 Another type of CD8q Ts cells was generated in vitro from purified circulating CD8q lymphocytes incubated for 1 week with monocytes, IL2 and GM-CSF. Ts cells inhibited the proliferative response of T cells stimulated with specific antigens, anti-CD3 monoclonal antibodies or mitogens w18x. Furthermore, they also seem to suppress the lysis mediated by cytotoxic cells (Filaci et al., unpublished). The mechanism of action of this subset of CD8q suppressor cell is not yet completely understood, although it is clear that they exert their function through soluble factors without direct interaction with APC. Thus, when separated
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
281
Fig. 1. Schematic representation of the three subpopulations of CD8q T suppressor cells identified in humans. Upper row: The type 1 of CD8q T suppressor cells recognize the HLA class I-antigen complex on dendritic cells and induce down-modulation of costimulatory functions. Middle row: The type 2 of CD8q T suppressor cells are generated by incubation with IL2 and GM-CSF and induce inhibition of CD4q T cell proliferation through secretion of IFNg and IL6. Lower row: The type 3 of CD8q T suppressor ¨ CD8q T cells via secretion of IL10. cells are generated after interaction with (plasmocytoid) DC2 and induce inhibition of naıve
282
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
from the stimulated T cells by a pored membrane, which prevents direct cell-to-cell contact while allowing the passage of cytokines, their suppressor activity is not halted. Studies of intracellular cytokines revealed the presence of IFNg, IL6 and IL12. Using an anti-IFNg blocking antibody or oligonucletides antisense for the sequence of IL6 mRNA we could antagonize the suppressor function of these cells. Thus, IFNg and IL6 (directly or through the induction of others cytokines) are involved in the inhibition of T cell proliferation mediated by this subset of CD8q T suppressor cell w11x. Our still unpublished data suggest that generation of these cells does not require MHC recognition. Thus, it is possible to generate CD8q T suppressor cells using allogeneic monocytes from an HLA class I unmatched donor. It is unclear which lymphocyte subpopulation contains the circulating precursors of these cells. Healthy subjects have CD8qCD28q and CD8qCD28y T cell subpopulations almost equally distributed in the peripheral blood. The CD8q T suppressor cells, that are CD28y, could derive from the former subpopulation, via the down-regulation of the CD28 molecule, or from the latter subset, that is already CD28y. Recent evidences suggest that when CD8qCD28q cells are separated from CD8qCD28y cells, generation of suppressor cells was possible only from the latter but not from the former cell subset. This suggests that the noncommitted circulating CD8qCD28y cells represent the source for generation of suppressor cells in tissue sites of inflammation andyor in lymph nodes (Filaci et al., unpublished). Preliminary studies suggest that the percentage of CD8qCD28y cells decreases in patients with systemic autoimmune diseases (SLE and systemic sclerosis) during relapses. It is therefore possible that during phases of disease reactivation the CD8qCD28y pool of T cells is depleted of suppressor cells andyor that CD8qCD28y suppressor T cells home into tissues and lymph nodes leaving the circulation (Filaci et al., unpublished). Future studies may elucidate the reason why impairment of CD8q Ts generation occurs in patients affected by SLE and multiple sclerosis during relapses w11,18x. Attempts to generate CD8q T suppressor cells from patients with active SLE have failed,
resulting in the expansion of T cells that showed no inhibitory activity and secreted reduced IL6 and increased IL12 amounts. 5. CD8H T suppressor cells: type 3 A third subpopulation of CD8q suppressor lymphocytes has been recently identified w19x. These cells were generated by stimulating purified, naive CD8q T lymphocytes with plasmacytoid dendritic cells (DC2). Their generation depends on antigen presentation and secretion of IL10 by DC2. DC2primed T cells develop energy to further stimulation with the same antigen and start secreting IL10 ¨ themselves. Their inhibitory activity affects naıve but not preactivated CD8q T cells and is directly mediated by IL10. The phenotype of these cells and their clinical relevance have not been analyzed (Fig. 1). 6. Conclusions Data obtained in the last 10 years demonstrate that immune homeostasis is controlled by several regulatory T cell subsets. Functional alterations of these cells may be associated with the onset of autoimmune phenomena. These findings are adding clues to our understanding of the pathogenesis of autoimmune diseases, which may result from an impaired balance between effector and regulatory cells. Study of immunoregulatory mechanisms may be crucial to the development of new strategies for treatment of autoimmune disorders. 7. Summary In recent years three different CD8q T suppressor cell subpopulations have been identified and functionally characterized in humans. Each of these suppressor subsets act in different ways to regulate antigen-specific T cell responses. Functional alterations were shown to be associated with the relapse of autoimmune diseases and onset of acute rejection episodes in transplanted recipients. A better understanding of immunoregulatory mechanisms is crucial to treatment of autoimmune diseases.
G. Filaci, N. Suciu-Foca / Autoimmunity Reviews 1 (2002) 279–283
Acknowledgments This study has been supported by grants from Ministero della Sanita’-Istituto Superiore di Sanita’, programma nazionale di ricerche sull’AIDS 1999 (n. 30C.39), and by MURST National Program ‘Meccanismi umorali e cellulari di modulazione dell’immunoflogosi’ (n. 9706117821-001). Take-home messages ● Three CD8q T suppressor cell (CD8q Ts) populations, inhibiting the proliferative activity of antigen-specific T lymphocytes, have been identified in humans. ● The types 1 and 2 of CD8q Ts are phenotypically characterized to be CD8qCD28y cells. ● The type 1 acts by down-modulating the expression of co-stimulatory molecules on dendritic cells. ● The type 2 inhibits proliferation via cytokine secretion (IFNg and IL6). ● The type 3 function is IL10-dependent. ● Numerical andyor functional alterations of type 1 or type 2 of CD8q Ts have been demonstrated in patients rejecting transplanted organs or in patients suffering for relapses of autoimmune diseases such as SLE and MS, respectively.
References w1x Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of cd4(q)cd25(q) t cells with regulatory properties from human blood. J Exp Med 2001;193:1303 –10. w2x Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AK. Identification and functional characterization of human cd4(q)cd25(q) t cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285 –94. w3x Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245 –52. w4x Pulendran B, Maraskovsky E, Banchereau J, Maliszewski C. Trends Immunol 2001;22:41 –7. w5x Gershon RK, Kondo K. Infectious immunological tolerance. Immunology 1971;21:903 –13.
283
w6x Damle NK, Engleman EG. Antigen-specific suppressor T lymphocytes in man. Clin Immunol Immunopathol 1989;53:S17 –S24. w7x Sercarz E, Krzych U. The distinctive specificity of antigen-specific suppressor T cells. Immunol Today 1991;12:111 –8. w8x Yuen MH, Protti MP, Diethelm-Okita B, Moviola L, Howard JF, Conti-Fine BM. Immunoregulatory CD8q cells recognize antigen-activated CD4q cells in myasthenia gravis patients and in healthy controls. J Immunol 1995;154:1508 –20. w9x Sun D, Qin Y, Chluba J, Epplen JT, Wekerle H. Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T–T cell interactions. Nature 1988;332:843 –5. w10x Liu Z, Tugulea S, Cortesini R, Suciu-Foca N. Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8qCD28y T cells. Int Immunol 1998;10:775 –83. w11x Filaci G, Bacilieri S, Fravega M, et al. Impairment of CD8q T suppressor cell function in patients with active systemic lupus erythematosus. J Immunol 2001;166:6452 –7. w12x Ciubotariu R, Colovai AI, Pennesi G, et al. Specific suppression of human CD4q Th cell responses to pig MHC antigens by CD8qCD28y regulatory T cells. J Immunol 1998;161:5193 –202. w13x Jiang S, Tugulea S, Pennesi G, et al. Induction of MHCclass I restricted human suppressor T cells by peptide priming in vitro. Hum Immunol 1998;59:690 –9. w14x Colovai AI, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N. Induction of xenoreactive CD4q Tcell anergy by suppressor CD8qCD28y T cells. Transplantation 2000;69:1304 –10. w15x Liu Z, Tugulea S, Cortesini R, Lederman S, Suciu-Foca N. Inhibition of CD40 signaling pathway in antigen presenting cells by T suppressor cells. Hum Immunol 1999;60:568 –74. w16x Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by Ts cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 2002;3:237 –43. w17x Ciubotariu R, Vasilescu R, Ho E, et al. Detection of T suppressor cells in patients with organ allografts. Hum Immunol 2001;62:15 –20. w18x Balashov KE, Khoury SJ, Hafler DA, Weiner HL. Inhibition of T cell responses by activated human CD8q T cells is mediated by interferon-g and is defective in chronic progressive multiple sclerosis. J Clin Invest 1995;95:2711 –9. w19x Gilliet M, Liu Y-J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 2002;195:695 –704.