CD8 T-Cells Are Not Essential for the Induction of “Low-Dose” Oral Tolerance

doi:10.1006/clin.1996.0029

Clinical Immunology and Immunopathology

Volume 78, Issue 2, February 1996, Pages 196-202

Clinical Immunology ...

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Abstract

To examine whether CD8 T-cells are essential for the induction of “low-dose” oral tolerance, we tested animals deficient in CD8 T-cells, i.e., Lewis rats in which CD8 cells were eliminated by injections of specific antibodies and β2m(−/−) mice in which the CD8 cells are scarce and poorly functional. Oral tolerance was induced in the rats by repeated feedings with the uveitogenic retinal S-antigen, while in the mice the fed antigen was ovalbumin. Feeding reduced in both species the specific cellular immune response, measured by the lymphocyte proliferation assay. In the rats, this treatment also inhibited the development of the inflammatory eye disease, experimental autoimmune uveoretinitis. In addition, the levels of specific antibodies in the fed animals were moderately lower than those in their controls. Both the CD8-depleted rats and the β2m(−/−) mice resembled their normal controls in demonstrating reduced immune responses following feeding with the corresponding antigen. This observation thus indicates that CD8 T-cells are not essential for the induction of low-dose oral tolerance.

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Cited by (31)

Oral tolerance: an updated review
2022, Immunology Letters
Citation Excerpt :
C) Dendritic cells. As mentioned above and simplified in Fig. 1, intestinal DCs are responsible for presenting the antigen sampled in the gut to cognate naïve CD8+ and CD4+ T cells in the MLN, though the role of CD4+ T cells appears to be more important for oral tolerance induction than CD8+ T cells [35–40]. Several subtypes of gut DCs have been described and they are located in small and large intestine lamina propria as well as in PP and in MLN.
Oral tolerance (OT) has classically been defined as the specific suppression of cellular and/or humoral immune responses to an antigen by prior administration of the antigen through the oral route. Multiple mechanisms have been proposed to explain the induction of OT including T cell clonal depletion and anergy when high doses of antigens are fed, and regulatory T (Treg) cell generation following oral administration of low and repeated doses of antigens. Oral antigen administration suppresses the immune response in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis, uveitis, thyroiditis, myasthenia, arthritis and diabetes, but also non-autoimmune inflammatory conditions such as asthma, atherosclerosis, graft rejection, allergy and stroke. However, human trials have given mixed results and a great deal remains to be learned about the mechanisms of OT before it can be successfully applied to people. One of the possible mechanisms relates to the gut microbiota and in this review, we will explore the cellular components involved in the induction of OT and the role of the gut microbiota in contributing to OT development.
Mechanisms of Oral Tolerance to Soluble Protein Antigens
2015, Mucosal Immunology: Fourth Edition
The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Although most immune cells present in the gut display an activated state, in physiological conditions tolerance induction is the default immune pathway at this site. Immunological tolerance to antigens that gain access to the body via the oral route has been termed “oral tolerance” and appears to be physiologically important to prevent intestinal disorders, such as food allergy, celiac disease, and inflammatory bowel disease. Because of its unique immunological properties, oral tolerance is an attractive approach for the development of nontoxic and more effective treatments for different inflammatory and autoimmune diseases. Here we review the basic mechanisms underlying the establishment and maintenance of oral tolerance and discuss the potential to translate it more effectively to the clinic.
Induction of mucosal tolerance in SLE: A sniff or a sip away from ameliorating lupus?
2009, Clinical Immunology
Citation Excerpt :
Alternatively, priming of CD8+ T cells with regulatory properties in the gut can occur via presentation of fed antigens by mucosal DCs in the context of a MHC Ib molecule Qa-1 that is able to recognize self antigens and bacterial heat shock proteins [118,119]. The role of CD8+ T cells have also been examined using genetically engineered CD8 deficient mice [120–122] and in mice treated with anti-CD8 antibodies [109,110,123]. In all the studies, oral tolerance was induced normally suggesting that there is no absolute requirement for CD8+ T cell in the induction or maintenance of systemic tolerance.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by aberrant immune responses against intracellularly derived self antigens. Treatment for SLE relies on the use of aggressive immunosuppressants and steroids that are nonspecific and can cause serious adverse effects. The observation that a systemic immune tolerance to self antigens or generation of regulatory T cells may follow mucosal (nasal or oral) exposure to self proteins or monoclonal antibody against CD3 respectively suggests that induction of mucosal tolerance offers the basis of a side effect-free therapy that could re-establish the ability to distinguish self from non-self and restore peripheral tolerance in individuals susceptible to developing autoimmune diseases. Here I review studies on mucosal tolerance in autoimmune diseases and discuss the therapeutic potential of inducing tolerance for the treatment of SLE.
Suppression of Th1 and Th17, but not Th2, responses in a CD8<sup>+</sup> T cell-mediated model of oral tolerance
2009, Mucosal Immunology
The role of CD8⁺ T cells in oral tolerance remains unclear. To address this, we developed a model to induce CD8⁺ Tregs by feeding the major histocompatibility complex class I immunodominant epitope of OVA, OVA_(257–264). OVA_(257–264) feeding induced tolerance similar to that observed in OVA protein-fed mice, capable of suppressing the production of Th1 and Th17 cytokines and inhibiting a Th1-driven delayed-type hypersensitivity response following immunization with whole OVA (wOVA) protein. OVA_(257–264) peptide-induced suppression could be transferred to naive mice with CD8⁺ cells, but not CD8-depleted cells, isolated from mesenteric lymph nodes of peptide-fed mice. Interestingly, while capable of inhibiting Th1 and Th17 responses, OVA_(257–264) feeding could not suppress any feature of a Th2 inflammatory response, though OVA protein feeding could, suggesting that these cells function through a different mechanism than their CD4⁺ counterparts generated in response to feeding with wOVA. Thus, CD8⁺ T cells are functionally capable of mediating tolerance to Th1 and Th17 responses.
Initiating mechanisms of food allergy: Oral tolerance versus allergic sensitization
2007, Biomedicine and Pharmacotherapy
Citation Excerpt :
Distinct functional subsets of CD8+ cells have been described that may contribute to oral tolerance induction [160–162]. However, their functions have not been clearly defined and there is no absolute requirement for CD8+ T cells in the induction or maintenance of oral tolerance [163]. Another T cell subtype in the immunoregulatory network is represented by the NK T cell that shares properties of NK cells and conventional T cells and is associated with CD1d-restricted responses.
Immediately after birth the mucosa of the gastrointestinal tract, which represents the greatest body surface area exposed to the outside environment, is confronted with a large variety of foreign antigens. The immune system of the intestine now has to meet the task of discriminating between pathogens and harmless antigens, such as food proteins and commensal bacteria, and to respond accordingly. This important job is fulfilled by cells of the gut-associated lymphoid tissue, the largest immunologic organ in the body.
Despite the large extent of food antigen exposure, only a small percentage of individuals experience adverse immunologic reactions to food. This is due to the fact that the normal immune response to dietary proteins is associated with the induction of oral tolerance, which refers to a state of active inhibition of immune responses to an antigen by means of prior exposure to that antigen via the oral route. Abrogation of oral tolerance or failure to induce oral tolerance may result in the development of food hypersensitivity. In the present review, factors that may play a role in the outcome of oral tolerance versus sensitization to food proteins are discussed.
Oral tolerance physiologic basis and clinical applications
2005, Mucosal Immunology, Two-Volume Set

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¹: To whom correspondence should be addressed at NEI, NIH, Bldg. 10, Rm. 10N208, Bethesda, MD 20892-1858. Fax: (301) 402-0485.

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Regular ArticleCD8 T-Cells Are Not Essential for the Induction of “Low-Dose” Oral Tolerance

Abstract

Regular Article
CD8 T-Cells Are Not Essential for the Induction of “Low-Dose” Oral Tolerance