T Cells:Regulation and Cellular Immunity
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
The “two signal theory” of lymphocyte activation proposed by Bretscher and Cohn some twenty years ago states that immune cells are activated by an antigen-specific signal (“signal 1”) derived via interaction with the immune receptor (Ig or TCR) and a non-specific signal (“signal 2”) mediated either by a cellular contact or soluble factor (cytokine). The theory further states that signal 1 alone is “paralytic,” i.e., in the absence of simultaneous signal 2, the cell will be rendered incapable of responding to future activating signals. This results from a long-lasting, or perhaps even permanent, alteration in the signalling machinery. This condition of unresponsiveness is called anergy. A large body of experimental evidence supports this model, and it is generally consistent with the schemata of activation presented in Chapter 5 for B cells and above for T cells. For T cells in particular, it is hypothesized that a special type of “defective” antigen-presenting cell may exist for the induction of anergy. This cell would present self peptides, but lacking appropriate co-stimulatory signals, could only deliver signal 1, thus rendering interacting T cells anergic. The two signal model of lymphocyte activation also applies to γδ T cells.
Shifting Paradigms in Peripheral Tolerance
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
Not all T cells die following activation. In the absence of costimulation, a cohort often remains that is hyporesponsive upon rechallenge.16-19This state of functional inactivation is referred to as anergy. T cell clonal models in vitro have shown that anergic cells have a block in T cell receptor (TCR) signal transduction through the Ras/mitogen-activated protein (Ras-MAP) kinase pathway, a defect which in conjunction with other alterations leads to inhibition of transcription of genes involved in proliferation, such as interleukin-2 (IL-2).34 This state is stable in the absence of antigen. In vivo, however, the mechanisms for anergy are less clear and may be multifactorial. All cytokine production seems to be down-regulated and the state is reversible in the absence of antigen.18,21,22,35 The immune system appears to be holding these cells in check awaiting further signals, such as an increase in antigen concentration, before determining their fate. In the presence of other T cells and the persistence of antigen at the same level, the anergic cells eventually disappear.36
Clinical Applications of Thymic Hormones, Current Status, and Perspectives
Marek P. Dabrowski, Barbara K. Dabrowska-Bernstein in Immunoregulatory Role of Thymus, 2019
In contrast to the rapidly progressing defect of T helper/inducer cells, CD8+ cytotoxic/suppressor T lymphocytes and humoral immunity remain relatively less damaged. In some aspects, advanced AIDS resembles the symptoms of a wasting disease observed in neonatally thymectomized animals, the state of immune anergy in homozygotic nude mice, or the severe combined immunedeficiency disease in man. The common immune defects relate to the profound injury or to the absence of thymic tissue and to the impairement of T lymphocyte development at an early stage of differentiation. The most profound defects of this sort were observed in some patients with SCID, whose peripheral lymphocytes were lacking CD 10, CD3, CD4, CD6, CD8, and CD2 antigenic markers or represented the cell surface phenotype CD10+ with CD2+ or CD2− and without all the remaining T cell markers.84 Attempts to induce differentiation of these cells along the T cell pathway under the influence of thymosin TF-5 or in contact with cultured thymic epithelial monolayers succeeded in the expression of CD10 antigen only, pointing to the existence of a true block of differentiation, presumably at the level of transition of prothymocytes to thymocytes.
Annexin-coated particles induce antigen-specific immunosuppression
Published in Autoimmunity, 2020
Corinna Link, Fatmire Bujupi, Peter H. Krammer, Heiko Weyd
Alternatively, the reduced T cell response may be explained by induction of T cell anergy. Anergy is a state of unresponsiveness, mainly described by attenuated proliferation and cytokine production [9] which corresponds to the observations in Figure 1. In order to test the hypothesis that Anx-bead-treated DC induce T cell anergy, additional markers associated with an anergic phenotype were analysed. Although IL-2 dysregulation is a hallmark of anergy [9,12] and IL-2 mRNA expression in T cells was reduced by Anx-bead treated BMDC as early as 4 h after co-culture, mRNA expression of anergy-related genes were not found to be significantly upregulated (Figure 4(D–H)). Nevertheless, the regulation of T cell proliferation and cytokines, especially IL-2 on protein and gene expression level, indicate that Anx-bead-treated BMDC induce an anergy-like phenotype in OT-II T cells.
Challenges in Treating Intraocular Inflammation in HIV Patients
Published in Ocular Immunology and Inflammation, 2020
Ilaria Testi, Safia Ahmed, Camrun Shah, Rupesh Agrawal
Similarly, the value of the purified protein derivative (PPD) skin test in patients infected with HIV could be limited by the anergy of the host induced by the virus. It is well known that anergy correlates with CD4 + T-lymphocyte count and the lower the count, the higher the prevalence of anergy. Anergy in HIV-infected patients derives from the ability of HIV envelope glycoprotein moieties to bind to CD4 + T-lymphocyte molecules and chemokine receptors, interfering with antigen presenting cell function and leading to a malfunction of the positive and negative molecules involved in the signal transduction pathway.27 Janis et al. analyzed the PPD skin response of 310 hospitalized subjects.28 Sixty-two of 310 patients (20%) had a skin response of more than 10 mm of induration.28 Fifty-two patients were infected with HIV and none of them had a positive PPD skin test result.28 Anergy was detected in 63% of the HIV subjects compared to 28% of non-HIV patients.28 Since the PPD skin test is still widely used as an important test for diagnosing tuberculosis and HIV infection, it appears as an independent risk factor for the development of anergy. Hence, care should be taken when interpreting a negative PPD skin test in immunocompromised patients.
Polyphenol containing Sargassum horneri attenuated Th2 differentiation in splenocytes of ovalbumin-sensitised mice: involvement of the transcription factors GATA3/STAT5/NLRP3 in Th2 polarization
Published in Pharmaceutical Biology, 2021
Kalahe Hewage Iresha Nadeeka Madushani Herath, Jinhee Cho, Hyo Jin Kim, Duong Thi Thuy Dinh, Hyun-Soo Kim, Ginnae Ahn, You-Jin Jeon, Youngheun Jee
STAT5 activation also drives the expression of NLR family pyrin domain containing 3 (NLRP3), a component of the inflammasome, and home to the nucleus promoting the transcription of genes encoding IL-4, IL-5, and IL-13 in T cells (Ting and Harton 2015). The transcriptional upregulation of STAT5, NLRP3, and GATA3 was revealed to be a key event in Th2 differentiation (Zhu 2015). Immunotherapy for certain conditions, such as atopy in children and perennial allergic rhinitis, typically works via the induction of tolerance or anergy to Th2 cells (Tanaka et al. 1998; Smart and Kemp 2002). In particular, natural sources to attenuate the function of pathogenic Th2 cells and their released cytokines have undoubtedly revolutionised the interest in immune therapy due to the cost effectiveness and absence of adverse effects (Li et al. 2000; Chitnis et al. 2004).
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- Immune Tolerance
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