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• W2114811089 abstract "Historically, CD8 T cells have been divided into cytotoxic T cells and suppressor T cells. Cytotoxic CD8 T cells have been regarded as a homogeneous population of CD4-dependent cells producing a limited number of cytokines – namely interferon (IFN-γ), tumour necrosis factor (TNF-α) and lymphotoxin. Their function was thought to be restricted to defence against viral infections and intracellular pathogens. CD8 suppressor T cells were considered a functionally distinct population of CD8 T cells, which switch off established immune responses or maintain tolerance to particular antigens.1-4 The idea of suppressor T cells first arose in the late 60s and early 70s, when early work of Gershon and colleagues showed that adoptive transfer of T cells from animals tolerant to a particular antigen could specifically suppress antibody production (against that particular antigen) in the recipient animals.5, 6 The advances in immunology during the 1970s led to the idea that distinct T cell functions were mediated by distinct subsets of T cells, expressing different cell surface molecules. These findings were further extended to other species, and it was subsequently proposed that cytotoxic and suppressor populations belonged to the CD8 T-cell subset.7-10 In the early studies in both mice and human models suppression was shown to require interaction between CD8 and CD4 T cells. It was proposed that activated CD4 T cells were required for the induction of the CD8 suppressor cells11, 12 which then mediate suppression by inhibiting functions of the inducing CD4 T-cell population. These experiments led to models in which very complex cellular circuits were proposed13-16 involving a confusing array of suppressor cells, factors and mechanisms. To this day the existence of these putative antigen (Ag)-specific suppressive factors has not been resolved leading to widespread dismissal of the existence of suppressor cells.17 However, CD8 T-cell-mediated suppression has been clearly demonstrated in a number of systems including: antibody responses to soluble and cellular antigens,18-20 responses to superantigens,21, 22 graft-versus-host disease (GVHD),23 allograft rejection,24 asthma (virus induced)25 and in oral tolerance.26, 27 More recently, a number of groups have demonstrated that human, murine and rat CD8 T cells have the potential to produce a much wider array of cytokines than was initially thought. Moreover, CD8 T cells appear to differentiate in a polarized fashion and can be divided into subsets analogous to those described for CD4 T cells. These subsets were termed type 1 or Tc1 and type 2 or Tc2.28, 29 However, while in the CD4 cells, different cytokine profiles were closely associated with specific functions, i.e. T helper type 1 (Th1) cells were inflammatory T cells, while T helper type 2 (Th2) cells were helpers for antibody production, a correlation between cytokine profile and function has yet to be clearly defined for CD8 T cells. Furthermore it is difficult to associate the newly described CD8 T-cell subsets with phenomena of immune suppression. However, as some CD8 T cells produce potent immunoregulatory cytokines such as interleukin-4 (IL-4),30 IL-1031 and transforming growth factor-β (TGF-β),32 it is likely they may play a role in immune regulation including suppression. In addition, more and more evidence has emerged indicating that CD8 T cells have the capacity to regulate both the induction and effector phases of the immune response through their secreted products or through direct interaction with other cells. Here, we review evidence, old and new, for the capacity of CD8 T cells to influence the outcome of numerous immune responses. The regulatory interactions between CD8 T cells and CD4 T cells are complex and may involve both Ag-specific and non-specific mechanisms. Antigen-specific regulation could, in principle, occur in two ways: both CD4 and CD8 T cells may recognize antigen–major histocompatibility complex (Ag–MHC) complex on conventional antigen-presenting cells (APCs). Activated CD8 T cells would then suppress or inactivate CD4 cells in the proximity, by either secreted products or cell contact, or possibly by killing of the APC. Alternatively, CD8 T cells may recognize activated CD4 T cells directly, in a peptide-specific manner. Activated regulatory CD8 T cells would, in turn, delete or otherwise inactivate ‘inducer’ CD4 T cells. CD8 T cells normally see antigen presented in the context of MHC class I and therefore are classically associated with immune responses to antigen generated in the cytosol, derived from cellular or viral protein inside the presenting cell.33 However, several groups demonstrated the ability of exogenous protein antigens to be presented to CD8 T cells in the context of MHC class I.34-36 It has been shown that in both macrophages and dendritic cells proteins from the phagosome can leak into the cytosol and therefore into the class I pathway.36-38 Once such leakage has occurred, the mechanism by which exogenous proteins are processed and presented in the context of MHC class I is identical to that seen in the presentation of classical endogenous peptides such as viral particles.39 In this way it may be possible for CD8 regulatory T cells to recognize the same exogenous antigens which also activate CD4 T cells, for example in the case of ovalbumin (OVA)-specific CD8 T cells that suppress immunoglobulin E (IgE) responses. A number of studies described regulatory/suppressor CD8 T cells, which recognize antigen presented in the context of MHC class II molecules. This is in contrast to the widely accepted differences in antigen presentation between CD4 and CD8 T cells. Class II restricted, suppressive, IL-4 secreting CD8 T-cell clones have been isolated from leprosy patients.3 Murine CD8 suppressor T-cell clones restricted by MHC class II have also been described.4 The mechanism by which CD8 T cells interact with MHC class II molecules is not clear, given the known importance of co-receptors in T-cell receptor (TCR)–MHC interactions. It is possible that certain TCRs interact in a co-receptor-independent fashion. This could enable CD8 T cells to recognize specific antigen at the same time as it is recognized by CD4 T cells. Suppressor CD8 T cells would then release inhibitory cytokines, which control the CD4 response. Alternatively, suppressor CD8 T cells may become activated as a consequence of a cognate interaction with Ag-activated CD4 T cells. There is considerable evidence that CD8 T cells downregulate CD4 proliferation in a TCR-Vβ-specific manner. This led to the hypothesis that regulatory CD8 T cells recognize TCR-related structures such as TCR-derived peptide–MHC complex expressed on activated CD4 T cells. For example, studies in staphylococcal enterotoxin B (SEB)-primed mice have shown that CD8 T-cell mediated depletion of the responding CD4+Vβ8+ T cells was Vβ specific: so that Vβ8+ but not Vβ8− CD4 targets were killed.40 Furthermore, these CD8 suppressor T cells were not restricted by classical MHC class I molecules. Instead, it was demonstrated that Ag was presented in association with a MHC class Ib molecule Qa-1, which is known to be capable of presenting endogenous as well as exogenous peptides. Vβ-specific CD8 T cells also exist in human peripheral blood and can be induced in vitro by SEB-activated CD4 T cell clones.41 These human CD8 T cells raised against a CD4 Vβ2+ T-cell clone specifically recognize and lyse Vβ2+, but not Vβ2−, CD4 target cells. This killing was not inhibited by antibodies against human class Ia molecules suggesting that non-classical MHC molecules may be involved in Ag presentation.41 Thus the following mechanism of Ag-specific suppression has emerged: after T-cell activation by Ag, TCR Vβ peptide binds to non-classical class I molecules (such as Qa-1) expressed on the surface of CD4 T cells. These CD4 T cells function as inducers of TCR Vβ-specific CD8 T cells, which in turn downregulate them (Fig. 1). As resting T cells do not express Qa-1/Vβ complex they are spared from the suppressive effects of regulating CD8 T cells, ensuring selective down-regulation of activated CD4 T cells. Model of activation and function of Qa-1-restricted regulatory CD8 T cells. CD8 T cells can interact with antigen-activated CD4 T cells in a T-cell receptor (TCR)-specific, Qa-1-restricted manner. CD4 T cells recognize antigen–major histocompatibility complex (Ag–MHC) complex on antigen-presenting cells (APCs), and become activated. Antigen-activated CD4 T cells start to express Qa-1 molecules in association with TCR-Vβ-derived peptides. CD8 T cells recognize Qa-1/Vβ complex on the CD4 T cells, and differentiate into regulatory CD8 T cells. Regulatory CD8 T cells downregulate ‘inducer’ CD4 cells. Regulatory cells can modulate the immune response by multiple effector mechanisms. In accordance with CD8 T-cell cytotoxic function, their immunoregulatory effects can be mediated by direct lysis or apoptosis induction of specific CD4 T-cell targets. Furthermore, immune regulation can be mediated by secretion of particular cytokines such as TGF-β, IL-10, IL-4 or IFN-γ, which act directly on the target CD4 cells as suppressive or differentiation factors. However, CD8 regulatory cells can also function in an indirect manner – by modifying the behaviour of antigen-presenting cells, which in turn influence the development/function of other effector cells. A number of studies provide strong evidence for a direct role of CD8 T cells in downregulation of CD4 T-cell responses to autoantigens and foreign antigens. In mice and rats experimental autoimmune encephalomyelitis (EAE) is directly caused by myelin basic protein (MBP)-responsive CD4 T cells. Mice that recover are protected from a second induction of the disease (by MBP immunization) and from recurrent relapses. Based on experiments with mice depleted of CD8 T cells, and CD8−/− mice, it is clear that CD8 T cells play a crucial role in inducing this resistance.21, 42 Furthermore, following vaccination with attenuated autoimmune T cells, regulatory CD8 T cells recognize and downregulate these vaccine T cells leading to acquisition of EAE resistance. These CD8 T cells inhibit proliferation and specifically lyse vaccine CD4 T-cell clones in vitro.43 Similarly, in multiple sclerosis patients, CD4 T-cell vaccination induced regulatory CD8 T cells.44 Jiang and colleagues have shown that prolonged depletion of peripheral Vβ8 CD4 T cells following SEB vaccination is dependent on CD8 T cells.40 Similar Vβ8-specific Qa-1-restricted CD8 T cells are also induced by T-cell vaccination with activated CD4+Vβ8+ T cells.45 Furthermore, CD8 T cells can suppress the immune responses to certain peptides derived from conventional antigens such as hen egg lysozyme.46 It is most likely that the mechanism of suppression of these immune responses is based on direct recognition and killing of Ag-specific inducer CD4 T cells; this could be via Fas or perforin-mediated pathways. In addition to direct targeting of CD4 T cells by cytotoxic CD8 T cells, suppression can also be mediated by enhancement of activation-induced cell death (AICD) in CD4 T cells. This occurs when T-cell activation results in apoptosis and can occur by fratricide. Recent data suggests that CD8 T cells can enhance apoptosis of autologous, superantigen-activated CD4 T cells via Fas–FasL interaction.47 In this case, CD8-mediated suppression is independent of class I expression but is nevertheless focused on responding CD4 T cells and not bystander cells. This is probably due to the fact that AICD susceptibility requires activation. Therefore CD8 T cells expressing high levels of Fas-ligand or producing other apoptosis-promoting molecules such as TNF-α48 could suppress antiself responses or prevent hypersensitivity to foreign antigen by inducing apoptosis in activated CD4 cells. Furthermore, as CD4 T-cell subsets are differentially susceptible to apoptosis, a further level of regulation exists whereby Th1 CD4 T cells would be preferentially removed. CD8 T cells are capable of secreting a number of cytokines, which may negatively regulate proliferation of CD4 T cells. Therefore, suppression may be mediated by the production of particular cytokines such as IL-4, TGF-β or IL-10.2, 4,26, 31 One of the clearest associations of a CD8 T-cell cytokine production with suppression is that seen in human leprosy. Interleukin-4-secreting CD8 T cells from lepromatous leprosy patients are able to suppress the proliferation of leprosy-specific CD4 T-cell clones in an IL-4-dependent manner. Similarly, Inoue et al. have described mouse CD8 suppressor T-cell clones that secrete high levels of IL-10.4 These cells also suppress CD4 proliferative responses, although other factors in addition to IL-10 could not be ruled out. CD8 T cells have also been shown to suppress both in vivo and in vitro immune response in models of oral tolerance. Studies in the Lewis rat model of EAE demonstrated suppression mediated predominantly by regulatory CD8 T cells through the release of TGF-β.26, 32 Similarly CD8 T cells play an important role in the induction of oral tolerance to MBP in mice.49 However in this case IL-4 and IL-10, in addition to TGF-β, may contribute to the suppression. The role for TGF-β-secreting, immunoregulatory T cells has also been demonstrated in models of transplantation tolerance. Donor-specific allograft tolerance, which can be induced in rats by donor-specific blood transfusion, is mediated by CD8 T cells secreting high levels of TGF-β.50, 51 CD8 T cells can also suppress proliferative responses of CD4 T cells by indirect mechanisms that do not involve direct deletion and are not mediated by cytokines. Antigen-specific human suppressor T cells have been generated in vitro by multiple rounds of stimulation with allogeneic, xenogeneic or antigen-pulsed autologous APCs.45, 52,53 These allospecific, xenospecific and nominal-antigen specific CD8+CD28− T cells suppress CD4 T-cell reactivity by inhibiting the costimulatory function of APCs. In this model the APCs expressing class II/Ag complex recognized by CD4 cells and class I/Ag complex recognized by CD8 suppressor T cells become unable to upregulate expression of costimulatory molecules such as CD80 and CD86.52, 53 Therefore, they are unable to initiate and sustain CD4 activation. Furthermore, it has been demonstrated that xenospecific suppressor T cells inhibit the CD40 signalling pathway by interfering with the expression of CD40L on xenoreactive CD4 cells.52, 54 It appears that activated suppressor T cells render CD4 T cells unable to produce IL-2 and that the suppressive effect of CD8 T cells can be prevented by the addition of exogenous IL-2. This suggests that by interfering with costimulatory interaction between Th cells and APC, suppressor T cells mediate the induction of an unresponsive state in CD4 T cells, which is similar to anergy.55 In addition, the findings that CD8 suppressor cells inhibit CD40L expression on xenoreactive CD4 T cells, suggests that it may prevent helper T cells from providing cognate help for macrophages and antibody-producing B cells. Hence suppressor T cells may effectively inhibit a range of T-helper-cell dependent effector functions. The ability of CD8 T cells to regulate the production of IgE is a well-recognized example of T-cell mediated suppression.18, 56-59 Various models of IgE response in both mouse and rats have demonstrated that functional abrogation of CD8 T cells by treatment with low-dose irradiation,60 or direct depletion with either toxic lectin ricin61, 62 or CD8-specific monoclonal antibodies20 enhances the total and specific IgE responses to alum-precipitated antigen. IgE inhibitory CD8 T cells have been generated following antigen inhalation58, 59 or parenteral immunization.63, 64 Further research in rat models confirmed the vital role played by CD8 T cells: adoptive transfer of CD8 T cells (or cell lines), generated from in vivo antigen-primed rats was shown to suppress IgE levels in CD8 T-cell-depleted recipient rats responding to OVA/alum immunization.18, 20,65 The mechanism of IgE suppression is unclear but appears to be linked to a deviation of a type 2 dominant, to a type 1 dominant immune response. Two important characteristics of CD8 T cells, cytotoxicity and IFN-γ secretion, have been investigated as a possible explanation for IgE suppression. It is difficult to correlate the classical cytotoxic function of CD8 T cells with their ability to regulate IgE. There is no evidence that CD8 T cells kill specific Th2 cells during a developing IgE response, which would effectively remove B-cell help.66 Alternatively cytotoxic CD8 T cells could kill Ag-specific B cells or APCs.35, 67 The most obvious explanation for the suppressive ability of CD8 T cells is the secretion of IFN-γ. IFN-γ could act directly on B cells to inhibit IgE synthesis or inhibit Th2 CD4 T cells. IFN-γ production during CD4 T-cell responses could inhibit the development of Th2 cells whilst favouring the development of Th1 cells.18 Depletion of CD8 T cells in immunized animals enhances antigen-specific IL-4 and suppresses IFN-γ synthesis,20 suggesting that CD8 T cells switch the CD4 T-cell response from Th2 to Th1. However, the ability of OVA-specific CD8 T-cell clones to inhibit IgE is unrelated to their cytolytic activity or the levels of IFN-γ they produce in vitro.65 Therefore, simple theories fail to provide an explanation for the mechanism behind CD8 T-cell-mediated suppression in these models. We have tried to address the question of the mechanism of CD8-mediated IgE suppression in a mouse model: both CD8 Tc1 and Tc2 cells from OT-1 TCR transgenic mice inhibited IgE responses68 (M.T et al. manuscript in preparation). Adoptive transfer of OVA-specific Tc1 and Tc2 cells into wild-type mice increased Th1 and inhibited Th2 cell numbers. The redundancy of CD8 T-cell derived IFN-γ was further demonstrated by the comparable levels of suppression observed when OVA-specific IFN-γ−/− CD8 T cells were adoptively transferred into wild-type mice. However, the suppressive mechanism does depend on the presence of IFN-γ-producing Th1 cells, thus demonstrating an ultimate requirement for IFN-γ. This was confirmed by adoptive transfer of OVA-specific CD8 T cells into IFN-γ knockout recipient mice, which could only inhibit the IgE response if naïve wild-type (IFN-γ competent) CD4 T cells were also transferred. In addition, IL-12 appears to play a critical role in IgE regulation as CD8 T cells failed to inhibit IgE responses in OVA-immunized IL-12−/− mice, unless reconstituted with naïve wild-type (IL-12 competent) dendritic cells (DC). Thus we propose the following mechanism of IgE suppression: CD8 T cells induce IL-12 production (by DC or other cells) that promote Th1 immunity and so inhibit IgE (Fig. 2) (M. J. Thomas, A. Noble, E. Sawicka, P. W. Askenase, D. M. Kemeny, manuscript in preparation). The mechanism by which CD8 T cells induce IL-12 production remains unclear. Novel mechanism by which CD8 T cells regulate immunoglobulin (IgE) responses. Ovalbumin is taken up by dendritic cells in the periphery which then migrate to lymphoid organs (a). Once there, ovalbumin (OVA) is processed and peptides presented in the context of both major histocompatibility complex (MHC) class I and class II molecules (b). Presentation of peptide to OVA-specific CD8 T cells facilitates further activation and the expression of costimulatory molecules such as CD40L and CD28 or survival factors such as TRANCE. IFN-γ production is not required (c). Interaction with the CD8 T cell induces the production of IL-12 by the dendritic cell (d). The IL-12-produced influences the differentiation of the OVA-specific CD4 T cell bound to the dendritic cell (DC), thus generating a T helper type 1 (Th1)-dominant response (e). The interferon-γ (IFN-γ) produced by the dominant Th1 cell population is sufficient to suppress the activity of any Th2 cells generated by OVA priming (f). The resulting suppression of Th2 cell activity reduces the degree of help available to B cells and prevents isotype switching to IgE (g). The above data and other findings suggest that, in addition to the ability of CD8 T cells to suppress CD4 proliferative responses, they may also regulate activation and differentiation of CD4 T-cell subsets. It is well established that the microenviroment plays a crucial role in directing the T-cell response towards type 1 or type 2 cytokine secretion. This may be due to the influence of secreted products (cytokines, chemokines) of resident cells or APCs, or to the nature of direct interactions, including TCR:ligand affinity, ligand density and costimulation. Therefore, CD8 T cells can influence the development of CD4 effectors both directly, through the production of secreted products, and indirectly through their action on other cells such as APCs. Many investigators have observed the role of CD8 T cells in determining the balance between Th1 and Th2 cells, primarily by the inhibition of IL-4-secreting cells.23, 69,70 As most CD8 T cells secrete a Th1-like pattern of cytokines, including copious amounts of IFN-γ, it is not surprising that CD8 T cells skew cytokine profiles of simultaneously activated CD4 T cells towards a Th1 phenotype. The regulatory role of CD8 T cells has been demonstrated in a number of Th2-mediated immune responses in vivo. For example, during the early course of acute and chronic murine GVHD, donor CD8 T cells play a crucial role. Rus et al. have demonstrated that the transition to acute GVHD is critically dependent on the engraftment of donor CD8 T cells which promote IFN-γ secretion from donor CD4 T cells.23 Furthermore, in the chronic GVHD model, enhanced expansion of CD8 T cells induced by a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade resulted in the downregulation of Th2-mediated humoral responses.69 Regulatory CD8 T cells, which recognize Qa-1 molecules on B cells have also been described in the mouse response to sheep erythrocytes. These cells secrete IFN-γ and inhibit Th2 antibody responses.19 Virus-specific CD8 T cells also downregulate Th2 cytokine secretion during murine respiratory syncytial virus (RSV) infection.25 The role of CD8 T cells in regulating the phenotype of Ag-specific CD4 T cells was confirmed by in vitro studies. Presence of CD8 T cells during stimulation prevented the development of IL-4-secreting CD4 T cells.70 Although this role for CD8 T cells in regulation of CD4 cytokine production is mostly mediated by secretion of IFN-γ, other factors, including cell contact, cannot be ruled out. The capacity of CD8 T cells to secrete type 2 cytokines is now established and murine, rat and human CD8 T-cell subsets analogous to Th1/Th2 subsets in CD4 populations have been described. As IL-4 is a crucial type 2 differentiating factor and may be inhibitory for Th1 development, it seems likely that Tc2 cells would have an opposite role on CD4 T-cell differentiation. This is in agreement with the observation that IL-4-secreting CD8 T cells generated from leprosy patients suppress Th1 proliferation. We have investigated the capability of human Tc1 and Tc2 clones to influence the development of CD4 effectors in vitro.71 In co-culture experiments, SEB-reactive Tc1 clones favoured the development of CD4 effectors that were Th1 biased, while Tc2 clones had the opposite effect. In addition, Tc2 and Tc1 clones efficiently suppressed the development of Th1 and Th2 cells, respectively. The observed effects are consistent with cytokine-mediated regulation, as Tc2 clones produced IL-4 and IL-10, and Tc1 clones secrete high levels of IFN-γ which could act directly or indirectly on developing CD4 cells. The involvement of cell contact, either direct, or via the APC, was not ruled out and is a matter for further investigation. However, it seems clear that through their secretion of IL-4 and IFN-γ, Tc2 and Tc1 cells can contribute to the cross-regulatory relationship that exists between Th1 and Th2 responses. In addition to cytokines, CD8 T cells secrete a wide array of chemokines that can act as chemoattractants and activators of particular T-cell subsets. For example, monocyte chemoattractant protein-1 (MCP-1) and regulated on activationnormal T-cell expressed and secreted (RANTES) enhance Th1 and CTL responses and increase IFN-γ and TNF-α secretion. Both IL-8 and macrophage inflammatory protein-1α (MIP-1α) are strong inducers of CD4 T-cell proliferative responses. However, IL-8 promotes Th1 response while MIP-1α shifts immune responses to Th2.72 Although we have so far concentrated mostly on the effects of regulatory CD8 T cells on CD4 T cells, CD8 T cells can also influence other inflammatory cells. CD8 T cells can regulate APC function, both through contact or through secreted products. CD40L/CD40 interaction has been shown to induce IL-12 synthesis by macrophages and dendritic cells.73-75 As at least some of the CD8 T cells (namely Tc2 cells) express CD40L, they are capable of inducing IL-12 production by macrophages and DC.71 As we have discussed, this can enhance subsequent IFN-γ production promoting Th1/Tc1 responses. Furthermore, it was recently demonstrated that CD8 T cells have the capacity to induce maturation of DCs.76 This may occur via tumour necrosis factor-related activation-induced cytokine (TRANCE) expression, a DC survival factor.77 TRANCE has been shown to upregulate production of IL-12, IL-15, IL-1 and IL-6 by DCs. Although expression of TRANCE in Tc1 and Tc2 cells has not been compared, it has been shown that IL-4-producing CD4 T cells downregulate TRANCE, leading to lower levels of IL-12, and downregulation of Th1 responses. A recent study by Aliberti and colleagues has identified MIP-1β as a potent inducer of IL-12 production on a subset of dendritic cells.78 Therefore, CD8 T cells could also enhance type 1-mediated responses, through secretion of MIP-1β. CD8 T cells can also contribute to and orchestrate type 2-mediated inflammation. CD8 T cells secreting type 2 cytokines (such as IL-4, IL-5 and IL-13) have been demonstrated to induce lung eosinophilia in models of murine choriomeningitis virus infection79 and in allergen or RSV-induced airway hyperresponsiveness.80, 81 Their effects are directly connected to the production of cytokines: IL-5 activates or primes eosinophils and prolongs their survival82, 83 while IL-13 and IL-4 can enhance eosinophil migration.84-86 CD8 T cells can also mediate immune regulation through the secretion of chemokines. For example, IL-8 is a potent neutrophil chemotactic factor while MIP-1α can chemoattract and degranulate eosinophils, and induce histamine release from basophils.87-89 Therefore, CD8 T cells, through the secretion of a range of biologically active molecules, can coordinate and regulate many cells of the innate immune system. Evidence for the ability of CD8 T cells to regulate immune responses is considerable; however, many questions about them remain. As discussed above, antigen specificity, mechanisms of antigen recognition, and mode of action await further clarification. Recently, functionally specialized regulatory T cells have been identified within the CD4 compartment (termed Th3, Tr1, Treg).27, 90,91 These regulatory CD4 T cells are involved in both mucosal tolerance and tolerance to self-antigens, and mediate suppression by secreting immunosuppressive cytokines TGF-β and/or IL-1092, 93 or by contact-dependent mechanisms.94-96 Furthermore CD45RBlow and CD25 have been implicated as phenotypic markers for regulatory T cells.91, 96,97 In the case of CD8 T cells, specific regulatory/suppressor phenotypes have not been clearly characterized. The separate suppressor CD8 population described in the early studies does not fit well in the Tc1/Tc2 paradigm and the existence of additional subsets similar to Th3 or Tr1 cells has so far not been described. It is unclear whether regulatory CD8 T cells belong to a discrete phenotypically and functionally distinct subset that can be identified by surface markers or secreted products. However, certain CD8 T cells clearly have the capacity to mediate immune regulation via numerous mechanisms." @default.
• W2114811089 created "2016-06-24" @default.
• W2114811089 creator A5000957116 @default.
• W2114811089 creator A5042020982 @default.
• W2114811089 creator A5056353942 @default.
• W2114811089 creator A5061565235 @default.
• W2114811089 date "2001-02-01" @default.
• W2114811089 modified "2023-09-26" @default.
• W2114811089 title "Specificity, restriction and effector mechanisms of immunoregulatory CD8 T cells" @default.
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