Contracting the immune response and peripheral tolerance
Definitions & Key takeaways
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.
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.
Fully developed T regulatory cells express co-inhibitory molecules like cytotoxic T-lymphocyte–associated antigen 4, or CTLA-4, on their surface.
CTLA-4 binds to and inhibits B7 molecules on antigen-presenting cells. This limits the ability of antigen-presenting cells to provide co-stimulation to the T cells, leaving them incompletely activated.
T regulatory cells also express high levels of IL-2 receptor and adenosine receptor - beating out other T cells, which also depend on IL-2 and adenosine for their proliferation.
That’s sort of like gobbling up all of the food before anybody else can get to it. The next mechanism of peripheral tolerance is clonal anergy.
The term “clonal” refers to the fact that only the set, or clones, of lymphocytes specific for an antigen, are affected by exposure to that antigen.
Anergy is the process of inactivating a lymphocyte when it binds to an antigen but doesn’t receive co-stimulation. This happens because self-antigens don’t induce the expression of B7 on antigen-presenting cells as much as foreign antigens.
T cells that come across antigens without receiving sufficient co-stimulation may go down two paths. First, their T-cell receptors, or TCR, that recognize antigens may lose their ability to send activating signals into the cell.
Second, the T-cells are stimulated to express CTLA-4, which acts as an internal fail-safe and further reduces the B7 availability.
Both the paths result in the inactivation, or anergy, of self-reactive T-cells. Yet another tolerance mechanism is the peripheral deletion, or elimination, of self-reactive T-cells through apoptosis or programmed cell death.
When T-cells repeatedly recognize self-antigens and experience a lack of co-stimulation, they produce less IL-2 and anti-apoptotic proteins that are normally required for their survival and proliferation.
This results in a relative deficiency of anti-apoptotic proteins and an excess of pro-apoptotic proteins within the cells, which initiates apoptosis.
Additionally, recognition of self-antigens may also increase the expression of death receptors and their ligands, for example, Fas and Fas ligand, on lymphocytes, which also promote apoptosis.Finally, the development of peripheral tolerance in B-cells is not clearly understood, but is thought to be mostly dependent on the lack of necessary stimulus for activation.
This is because B-cells that recognize self-antigens do not receive stimulation from T-cells, since they’ve already become tolerant.
A B-cell that doesn’t activate becomes anergic, and an anergic B-cell won’t differentiate into a plasma cell and won’t secrete antibodies.
A sustained lack of stimuli from T-cells may also cause the self-reactive B-cells to die. They may also undergo apoptosis through similar mechanisms as the T-cells.Alright, as a quick recap… T regulatory cells can inhibit the responses of all other immune cells by expressing CTLA-4 receptors that inhibit co-stimulatory B7 molecules on antigen-presenting cells.
Clonal anergy happens due to a lack of costimulation, because of the decreased expression and availability of B7 in the presence of self-antigens.
Peripheral deletion is when cells are induced to die because a cell surface marker called Fas is upregulated, initiating apoptosis.
As with T cells, peripheral tolerance in B-cells is achieved through anergy due to
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