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Contracting the immune response and peripheral tolerance

Contracting the immune response and peripheral tolerance


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High Yield Notes
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Contracting the immune response and peripheral tolerance

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Content Reviewers:

Rishi Desai, MD, MPH

The adaptive immune system, specifically the T- and B-cells, is the part of the immune system that is immunologically tolerant or unresponsive to self-antigens. Immunological tolerance can develop through two mechanisms- central and peripheral. Central tolerance mechanisms eliminate self-reactive lymphocytes during their initial development in the bone marrow and thymus. Peripheral tolerance mechanisms eliminate self-reactive lymphocytes that escape the radar of central mechanisms; in the peripheral tissues and secondary lymphoid organs. Failure of these mechanisms can result in autoimmune diseases like systemic lupus erythematosus.

The major peripheral tolerance mechanisms include T regulatory cells, clonal anergy, and peripheral deletion.

Now, the immune response is like a community of cells that fight together. Antigen-presenting cells, like dendritic cells, pick up antigens floating around in the body and serve them to naive T-cells, partially stimulating their activation. When the antigen is foreign, it strongly induces the expression of co-stimulatory proteins like the B7 on the antigen-presenting cell surface. B7 binds to the CD28 receptor on the naive T-cell and provides the additional stimulation needed to completely activate them, and also helps in their differentiation into specific types like effector or memory T-cells.

The CD4+ helper T cells are one of the most important immune cells. They secrete cytokines and provide signals that promote B-cell differentiation into plasma cells, class switching, and antibody production. CD4+ helper T cells also secrete cytokines that recruit phagocytes and help them kill more effectively. That’s why many of the peripheral tolerance mechanisms are aimed at shutting down CD4+ helper T cells.

Let’s start with T regulatory cells, which are able to inhibit the responses of all other immune cells. It’s thought that when a T cell responds a little too strongly to a self-antigen but not strong enough to be killed, it’s instructed to upregulate the transcription factor FOXP3, which guides its development into regulatory cells. Most T regulatory cells are “natural” T regulatory cells, meaning that they were selected to be T regulatory cells while developing in the thymus. While others are “acquired” T regulatory cells, meaning that they acquire this status out in peripheral lymphoid organs.


Peripheral tolerance refers to immunological tolerance developed after autoreactive T and B cells mature and enter the periphery. It enables the immune system to recognize and tolerate self-antigens or non-harmful foreign antigens in the body. Peripheral tolerance involves the suppression of autoreactive cells by 'regulatory' T cells, and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigens in the absence of the co-stimulatory signals that accompany inflammation, or in the presence of co-inhibitory signals.