AssessmentsContracting the immune response and peripheral tolerance
Contracting the immune response and peripheral tolerance
Decreased levels of lead to B-cell anergy, which means they won't mature into plasma cells.
Content Reviewers:Rishi Desai, MD, MPH
Ending an immune response is just as important as starting one.
The immune response begins with a single cell recognizing a dangerous intruder, and quickly expands into millions of cells.
Once a pathogen is eliminated, if the immune response isn’t stopped, it can lead to chronic inflammation which is damaging to the body.
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.
Most T regulatory cells are “natural” T regulatory cells, meaning that they were selected to be a T regulatory cell when they were developing in the thymus.
It’s thought that when a T cell responds a little too strongly to a self antigen but not strong enough to kill that cell, it’s instructed to upregulate the transcription factor FOXP3, which guides its development.
Fully developed T regulatory cells are able to inhibit antigen presenting cells like dendritic cells by releasing molecules like Indolamine 2,3 dioxygenase which interferes with tryptophan metabolism, and limits expression of receptors on the cell’s surface for co-stimulation and cytokines.
This inhibits antigen presenting cells from being able to present antigens, receive and provide costimulation, or receive survival signals and instructions to kill engulfed pathogens.
T regulatory cells also release cytokines like IL-10 and TGF-beta which induce antigen presenting cells, like dendritic cells, macrophages, and even B cells to express more inhibitory ligands like PD-L1 on their surface - sort of like putting the antigen presenting cell in an antisocial mood.
T regulatory cells also express high levels of IL-2 receptor and adenosine receptor - beating out other T cells for the IL-2 and adenosine. That’s sort of like gobbling up all of the food.
Anergy is the process of inactivating a lymphocyte when it binds to an antigen but doesn’t get a second signal called co-stimulation.
When an immune response is drawing to a close there’s often less co-stimulation, because cytokines produced by T regulatory cells make the antigen presenting cells express fewer B7 molecules on their surface.
This is sort of an internal fail safe where the T cell knows that at some point it will need to be turned off, so it upregulates a receptor to do that.
B7 binds to CTLA-4 twenty times stronger than it does to CD28.
When a T cell is first activated it has a lot of CD28 on its surface and very little CTLA-4, so B7 binds to the CD28 and the cell gets activated.
Clonal exhaustion is another way to inactivate a T cell.
When a T cell has been active for months to years, it begins to express the program death - 1 or PD-1 molecule on its surface. A way of showing off its veteran status.