AssessmentsContracting the immune response and peripheral tolerance
Contracting the immune response and peripheral tolerance
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.
The immune response is like a community of cells that fight together, and the leaders are the CD4+ helper T cells.
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.
The next mechanism of peripheral tolerance is clonal anergy and exhaustion.
Anergy is the process of inactivating a lymphocyte when it binds to an antigen but doesn’t get a second signal called co-stimulation.
For T cells, costimulation involves T cell’s CD28 molecule binding to B7 on the surface of the antigen presenting cell.
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.
In addition, as the immune response goes on T cells begin expressing the inhibitory molecule cytotoxic T lymphocyte associated protein 4 - or CTLA-4 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.
Over time, the T cell has a greater proportion of CTLA-4, so B7 ends up binding to CTLA-4 instead of CD28, and the cell gets inhibited, leading to T cell inactivation.
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.