What type of cell is T suppressor?

Given that T suppressor cell lymphopenia and lymphocytotoxic antibodies are common in SLE [163,164,172,182], it can be proposed that some cases of NP-SLE, including neurocognitive disorder, may be due to T cell/brain cross-reactive autoimmune responses, resulting in neuronal or glial cell loss, demyelination, and/or inflammation in the brain.

From: Systemic Lupus Erythematosus (Fourth Edition), 2004

Immune Tolerance in the Periphery

Tak W. Mak, Mary E. Saunders, in The Immune Response, 2006

III. CD8+ Ts CELLS

Ts (T suppressor) cells are a regulatory subset of CD8+ T cells distinguished by a marker profile of CD8+CD57+CD28−. (CTLs are CD8+CD57−CD28+; CD57 is a surface marker of unknown function found on NK cells and small numbers of peripheral T cells.) Ts cells were originally found to be increased in number after allogeneic transplantation or in patients infected with HIV or cytomegalovirus (where numbers of conventional CD4+ and CD8+ T cells are decreased), and decreased after radiotherapy or in patients suffering from autoimmune disease. Ts cells secrete a Th0-like profile of cytokines (including IL-2, IL-4, IFNγ, and TGFβ, but not IL-10) and can suppress the production of several antibody isotypes. However, rather than acting on effector lymphocytes like the CD4+ regulatory T cell subsets do, the most important effect of the Ts subset appears to be on APCs. Antigen-specific Ts cells that interact with an APC presenting peptides from the relevant antigen alter NF-κB-induced gene expression in the APC, causing it to suppress its expression of B7 molecules but upregulate expression of two surface receptors called ILT3 (immunoglobulin-like transcript 3; see Ch. 18) and ILT4. These surface receptors are expressed only by monocytes, macrophages, and DCs, and their appearance is associated with the ability of the APC to anergize, rather than activate, antigen-specific CD4+ Th0 cells, with which it subsequently interacts. This effect is strikingly similar to the modulation of DCs described previously, and indeed, treatment of APCs with IL-10 and IFNα can induce the expression of ILT3 and ILT4 by these APCs. Importantly, a CD4+ Th0 cell that interacts with an ILT3/ ILT4-expressing APC is induced to generate antigen-specific Th3 or Tr1 cells, propagating the tolerance. Studies in vitro by the transplantation research community (see Ch. 27) have confirmed that the interaction of an immature DC with an activated Ts cell directed against an alloantigen induces the upregulation of ILT3 and ILT4 on the DC, rendering it tolerogenic. Conventional alloreactive CD4+ T cells are subsequently anergized when they interact with these DCs presenting peptides from the alloantigen. It is unknown how Ts cells originate or what drives their development, but prolonged culture of peripheral blood cells (containing allogeneic APCs) of a prospective transplant with tissue from a prospective donor results in the generation of Ts cells in vitro. In vivo, heart transplant recipients that do not reject their new hearts have higher levels of circulating Ts cells than do those that reject their new organ.

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T-Cell Immunity

Jeffrey K. Actor PhD, in Elsevier's Integrated Review Immunology and Microbiology (Second Edition), 2012

T Regulatory/Suppressor Cells

Historically, cytotoxic suppressor cells were identified with function in regulating cellular (T cell) responses. Recently, it has become clear that this group represents a separate subpopulation of CD4+ lymphocytes generated in the thymus, which reflects consequent activities of T cells to produce cytokines that downregulate developmental pathways of TH responsiveness. This population is identified by expression of both the CD4 marker and the IL-2 receptor α chain (CD25), often with co-expression of CD45. Specific engagement of the TCR is required for function. Regulation is controlled via the transcriptional regulator Foxp3, mutations in which result in incidence of autoimmunity as well as uncontrolled lymphoproliferation. Mechanisms of immunosuppression/tolerance by CD4(+)CD25(+) Tregs include the local secretion of cytokines such as tumor growth factor–β and IL-10, and direct cell contact through binding of cell surface molecules such as CTLA-4 (CD152) on Tregs to CD80 and CD86 molecules on effector T cells.

Key Points About T Regulatory Cells

Tregs represent a population of CD4+CD25+ T cells that regulate effector T cells.

Tregs function through the transcriptional regulator Foxp3.

Loss or mutation in Foxp3 results in clinical manifestation of autoimmune disease and/or uncontrolled lymphoproliferation.

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HOST-PARASITE RELATIONSHIPS AND THE PATHOGENESIS OF INFECTIOUS DISEASES

Michael F. Tosi, in Feigin and Cherry's Textbook of Pediatric Infectious Diseases (Sixth Edition), 2009

REGULATORY T CELLS

The existence of T suppressor cells was long a subject of debate among immunologists. Only since the 1990s has solid evidence been developed to support the existence of suppressor T cells, now referred to as regulatory T cells. These cells were discovered when thymectomized mice were noted to develop autoimmune disease. Transfer of T cells that expressed CD25, the alpha chain of the IL-2 receptor, from normal adult mice to thymectomized mice prevented autoimmune disease. This population of CD4+CD25+ regulatory T cells can suppress the activity of other immune cells and has been shown to prevent graft-versus-host disease and allograft rejection. The mechanism of suppression by regulatory T cells is uncertain but may involve direct contact with other cells or secretion of inhibitory cytokines, including IL-10. These inhibitory cytokines can interfere with T-cell proliferation and inhibit the ability of antigen-presenting dendritic cells to promote T-cell activation. The role of regulatory T cells in immunity to infection is only beginning to be studied; some current evidence suggests that the action of regulatory T cells with specificity for microbial antigens may suppress protective immune responses to some infections but also may suppress excessive or injurious host responses.475

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Tolerance and Autoimmunity: T Cells

MATTHEW A. GRONSKI, PAMELA S. OHASHI, in The Autoimmune Diseases (Fourth Edition), 2006

Regulation by Other Cells

The existence of regulatory (suppressor) cells was postulated over 30 years ago following experiments using thymectomized mice and rats. These animals developed autoimmune destruction of the ovaries or thyroid gland, respectively, which could be prevented by adoptive transfer of normal CD4+ cells (Nishizuka and Sakakura, 1969; Penhale et al., 1973). Sakaguchi et al. (1995) showed that the autoimmune disease induced by the transfer of CD4+CD25− T cells into athymic nude mice could be prevented by the cotransfer of CD4+CD25+ T cells. These CD4+CD25+ T cells occur naturally and act by suppressing immune responses. The molecular basis of CD25+CD4+ suppression remains controversial. In vivo studies with knockout mice and blocking antibodies suggested a role for the cytokines IL-10 and transforming growth factor (TGF)-β in some models [reviewed in Sakaguchi (2004)]. In vitro suppression requires direct cell–cell interactions but it is not clear if this is also true in vivo (Read et al., 1998; Takahashi et al. 1998; Thornton and Shevach, 1998). Interestingly, CD4+CD25+ T cells constitutively express CTLA-4 and its blockade abrogates Treg function in vivo (Read et al. 2000; Takahashi et al., 2000). Thus, it is possible that more than one mechanism of suppression exists.

Further evidence for the importance of Tregs is provided by both human and animal models. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is an X-linked immunodeficiency syndrome associated with autoimmunity in multiple organs. The Scurfy strain of mice is an analogous disease model in mice displaying hyperactivation of CD4+ T cells and overproduction of proinflammatory cytokines. The defective gene has been identified as Foxp3, a member of the forkhead/winged-helix family of transcription factors (Bennett et al., 2001; Brunkow et al., 2001; Wildin et al., 2001). Further studies have suggested a role for Foxp3 in the development and function of natural CD4+CD25+ Tregs (Fontenot et al., 2003; Hori et al. 2003; Khattri et al., 2003). For example, CD4+CD25− T cells that were transduced with Foxp3 could suppress proliferation by other T cells in vitro and inflammatory bowel disease in vivo (Hori et al., 2003). Thus, Tregs appear to play an important role in the control of immune responses and autoimmunity.

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Primary Hyperparathyroidism

Claudio Marcocci, Filomena Cetani, in Encyclopedia of Endocrine Diseases (Second Edition), 2019

Cell division cycle 73 (CDC73) gene

Inactivating germline mutations of the tumor suppressor CDC73 gene, located at 1q31 encoding parafibromin, are responsible for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. The mutations are scattered along the entire coding region of the gene although most are located in exons 1, 2, and 7. The majority of the mutations are nonsense leading to a truncate parafibromin protein. Germline CDC73 mutations are also found in up to 15% of FIHP. Somatic mutations of this gene have also been reported in up to 70% of patients with sporadic parathyroid carcinoma, and in about one-third of them the mutation is germline. CDC73 mutations are very rare in sporadic parathyroid adenoma.

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Progressive Systemic Sclerosis

In Specialty Imaging: HRCT of the Lung (Second Edition), 2017

PATHOLOGY

General Features

Etiology

Reduced circulating T-suppressor cells and NK cells; may suppress fibroblast proliferation

Antitopoisomerase I (30%), anti-RNA polymerase III, and antihistone antibodies associated with interstitial lung disease

Anticentromere antibodies in CREST variant associated with absence of interstitial lung disease

Genetics

Postulated genetic susceptibility &/or environmental factors (silica, industrial solvents)

Overproduction and tissue deposition of collagen

Lung is 4th most common organ involved after skin, arteries, and esophagus

Staging, Grading, & Classification

American College of Rheumatology criteria: 1 major or 2 minor criteria required for diagnosis

Major criteria: Involvement of skin proximal to metacarpophalangeal joints

Minor criteria: Sclerodactyly, pitting scars, loss of finger tip tufts, bilateral pulmonary basal fibrosis

Microscopic Features

Pulmonary hypertension

Most distinctive finding: Concentric laminar fibrosis with few plexiform lesions

NSIP: Cellular or fibrotic (80%)

UIP: Fibroblast proliferation, fibrosis, and architectural distortion (10-20%)

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Peptide-Based Instruction of Suppressor Commitment in Naïve T Cells

IRINA APOSTOLOU, ... HARALD VON BOEHMER, in The Autoimmune Diseases (Fourth Edition), 2006

Publisher Summary

This chapter focuses on the generation of CD25+ suppressor cells by exogenous antigens in the fully mature immune system, as well as with their in vivo stability and function. Evidence suggests that CD25+ suppressor cells represent a suitable tool to induce antigen-specific immunologic tolerance in the fully mature immune system in the absence of general immune suppression, which often has undesired side effects ranging from increased risk of infection to development of life-threatening lymphoma. The fact that CD4+25+ FoxP3-expressing suppressor cells have an essential role in preventing the early onset of autoimmune disease in mammals, and the fact that these cells can be artificially induced through subimmunogenic presentation of TCR agonist ligands, opens new possibilities to exploit these cells to induce specific tolerance in the fully mature immune system. This may become a powerful tool in the prevention of allergies and transplant rejection. Inducing such cells by organ-specific antigens, may become an effective means to prevent autoimmunity in patients. However, such attempts have had success in animal models of disease but not in clinical trials.

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OVERVIEW OF CELLULAR IMMUNE FUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS

George C. Tsokos, in Systemic Lupus Erythematosus (Fourth Edition), 2004

T Suppressor Lymphocyte Function

Numerous studies have been performed to test the hypothesis that deficient suppressor cell activity is responsible for the uncontrolled production of autoantibodies by B cells and the subsequent development of autoimmunity. Concanavalin A-induced suppressor cell function in patients with SLE has been reported to be deficient [112–117] or normal [118, 119]. Concanavalin A-induced suppressor cell activity has been tested in a number of systems, including proliferative responses [117, 120, 121] and pokeweed mitogen-induced plaque-forming cell responses [114, 116, 122–124]. Deficient suppressor cell activity has been shown in the aforementioned studies to correlate with disease activity, serum DNA binding, low serum C3 levels, and treatment status. In procainamide and diphenylhydantoin-induced SLE, suppressor cell function is normal [125, 126]. Spontaneous and mitogen-induced nonspecific suppressor cell activity becomes normal during pregnancy in certain SLE patients [127].

Concanavalin A is a potent stimulus of T cells and, if not used under proper conditions (concentration, cell density, etc.), may not be sensitive enough to detect small differences among responding subpopulations. A number of studies have used more specific stimuli known to induce suppressor cell activity. EBV-associated suppressor/cytotoxic cell function is defective in patients with SLE who were seropositive to EBV [128]. Similarly, concanavalin A-activated T cells in some patients fail to suppress antitrinitrophenyl–Brucella abortus responses of autologous B cells [129].

Patients with SLE have severely impaired autologous mixed lymphocyte reaction responses (reviewed in Tsokos and Balow [32]). Deficient responses can be restored to normal levels if the responding cells are treated with exogenous IL-2 [130] or if the stimulatory non-T cells are pretreated with formalin-treated S. aureus or phorbol myristate acetate, suggesting that deficient responses may represent in part a failure of SLE non-T cells to present an appropriate stimulus for the generation of T-cell responses [131]. These studies indicate that (a) cellular abnormalities in patients with SLE can be detected when subtle stimuli (EBV, autoantigens) are used instead of more potent mitogens and (b) suppressor cell defects might be involved in the pathogenesis of SLE along with other cellular aberrations [32].

In one study, deficient concanavalin A-induced suppressor cell activity was found not only among SLE patients, but also in one-third of their relatives [115]. A major cross-reactive idiotype (16/6) among monoclonal anti-DNA antibodies has been identified. Antibodies carrying the 16/6 idiotype are increased in sera of patients with SLE and are deposited in the glomeruli and the skin. Schatner et al. [132] reported that some patients with SLE and their first-degree relatives have simultaneously defective suppressor cell function and increased levels of the 16/6 idiotype. They also found a correlation between the severity of the suppressor cell defect and the level of 16/6 idiotype carrying serum antibodies. However, increased 16/6 levels were commonly found in the presence of normal suppressor T-cell function. Despite these limitations, which imply that other factors must operate to cause tissue damage and clinical disease, these experiments strongly indicate a genetic input in the expression of cellular abnormalities in patients with SLE.

Impairment of CD8+ function in SLE patients has been attributed to an impaired secretion of IL-6 and IFN-γ and an increased production of IL-12 [133]. In the coculture system that was used to reach this conclusion, IL-6 and IFN-γ are responsible for the suppressor function of the CD8+ cells. These experiments have instigated a line of investigations that may lead to the validation of the earlier described defective suppressor cell function in SLE.

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T-Cells and Systemic Lupus Erythematosus

José C. Crispín, George C. Tsokos, in Systemic Lupus Erythematosus (Fifth Edition), 2011

Regulatory T cells

Regulatory T cells (Treg) are specialized CD4+ suppressor cells that express the transcription factor FoxP3 and the high-affinity IL-2 receptor (CD25). Treg may be selected in the thymus during the process of central tolerance or may be generated in the periphery from conventional CD4+ T cells that acquire a Treg phenotype under certain activation circumstances [115]. Treg maintain tolerance and limit immune responses and their absence causes a severe autoimmune disorder in mice and humans (IPEX) [116]. Quantitative and functional defects in Treg have been linked to several autoimmune disorders including SLE [117]. Most studies claim that reduced Treg numbers are observed in the peripheral blood of patients with SLE, particularly during active disease periods [118–120]. The suppressive function of SLE-derived Treg has also been studied, but the results are conflicting. Some reports claim they are unable to efficiently suppress proliferation and cytokine production [121, 122]. However, others suggest that their function is conserved and the suboptimal T-cell suppression observed in in vitro assays is the consequence of SLE T cells being abnormally resistant to Treg-induced suppression [123, 124].

These defects in Treg number and function may result from the altered cytokine milieu characteristic of SLE patients. Increased levels of the pro-inflammatory cytokines IL-6 and IL-21 combined with the decreased amounts of available IL-2 may decrease conversion of CD4+ T cells into Treg and inactivate their suppressive capacity, as suggested by studies in lupus murine models [125]. Treg defects may contribute to SLE pathology by failing to control T cell responses and autoantibody production [126].

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Th2/Th2/Th3 Cells for Regulation of Mucosal Immunity, Tolerance, and Inflammation

Kohtaro Fujihashi, Jerry R. McGhee, in Mucosal Immunology (Third Edition), 2005

Treg cells in mucosal tolerance

Several groups have recently focused on naturally occurring “T suppressor” cells using various models of organ-specific autoimmune or infectious diseases. In general, the suppressive activity is found in a rather large subset of CD3, αβ TCR+ CD4+, CD25+ T cells (Roncarolo and Levings, 2000). It is quite likely that Treg cells control mucosal immunity, tolerance, and inflammation to a higher degree than comparable Treg cells in peripheral lymphoid tissues. Generally speaking, Treg cells do not proliferate well in vitro, a characteristic reminiscent of anergic T cells. In fact, cloned anergic T cells can suppress the immune response in vivo and this appears to be in part due to effects on APCs (Chai et al., 1999; Taams et al., 1998; Vendetti et al., 2000). Thus, anergic T cells downregulate DC expression of CD80 and CD86 in a contact-specific fashion (Vendetti et al., 2000). Further, anergic T cells have been shown to produce IL-10, which is a major characteristic of some CD4+ CD25+ Treg cells (Sundstedt et al., 1997; Buer et al., 1998; Shevach, 2000; Sakaguchi, 2000) (Fig. 28.7). Thus, it appears that anergic T cells, through production of IL-10 (and perhaps through other mechanisms), develop into Treg cells that suppress immune responses to other antigens (Buer et al., 1998), a process sometimes termed “infectious tolerance” or “bystander suppression.” This may not be a universal pathway, however, because it was recently shown in an adoptive transfer model that CTLA-4 but not IL-10 expression was necessary for CD4+ T-cell tolerance (Fowler and Powrie, 2002) (Fig. 28.7). Despite their poor proliferative responses to Ag, it has been possible to induce populations of T-cell clones after incubation with IL-10 and alloantigen in humans (Groux et al., 1996) or to OVA peptide in DO11.10 mice (Groux et al., 1997). The T-cell clones obtained had similar properties, including secretion of high levels of IL-10, some production TGF-β1, with no IL-4 synthesis and poor proliferative responses (Maloy and Powrie, 2001) (Fig. 28.7). The precise locale for induction of anergic T cells is not known; however, the liver itself may contribute to this. For example, protein Ags given orally in high doses perfuse the liver. Further, oral delivery of a large OVA dose to OVA-Tg mice resulted in high numbers of apoptotic, OVA-specific CD4+ T cells in the liver (Watanabe et al., 2002). This led to the presence of CD4+ T cells secreting TGF-β1, IL-4, and IL-10, which could suppress T-cell proliferative responses (Watanabe et al., 2003). Cells with these characteristics are now termed Tr1 cells. The CD4+ CD25+Treg-cell subset can inhibit the development of EAE in MBP-Tg mice (Olivares-Villagomez et al., 1998) in a manner analogous to prevention of EAE by oral tolerance to MBP, and it is likely that Treg cells mediate some forms of oral tolerance. Thus far, Tr1 and Th3 cells have in common the production of TGF-β1 (Th3) or TGF-β1 plus IL-10 (Tr1) with suppressive-type properties.

What type of cell is T suppressor?

Fig. 28.7. Current proposed mechanisms of mucosal tolerance induction. For low dose tolerance induction, regulatory types of CD4+ T cells including TGF-β1 producing Th3 and CD25 positive Tr1 cells play central roles for active/bystander suppression. Meanwhile, anergy/clonal deletion of Ag-specific CD4+ T cells were induced by dendritic cell-mediated responses. CD4+, CD25+ Treg cells were also involved in these immune responses.

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What is the suppressor T cells?

What are Suppressor T cells? Suppressor T cells, which are now known as regulatory T cells, are a type of T cells that are found in the immune system. It is denoted as Treg. It helps in preventing autoimmune diseases and maintaining tolerance for self-antigens.

What type of cell is a suppressor cell?

Suppressor T cells play important roles in the regulation of immune responses and the mediation of dominant immunologic tolerance. Studies of suppressor T-cell function have been hampered until their recent identification as a minor fraction (approximately 10%) of CD4 ( +) T cells that coexpress CD25.

Are suppressor T cells CD4 or CD8?

Regulatory T cells (Treg) are specialized CD4+ suppressor cells that express the transcription factor FoxP3 and the high-affinity IL-2 receptor (CD25).

Are suppressor T cells CD8?

CD8 T suppressor (Ts) cells may directly inhibit other T cells or condition antigen-presenting cells in such a way that immune amplification steps are dampened. The great promise of CD8 Ts cells lies in their potential to disrupt host-injurious immune responses in a very targeted fashion.