In this video, we're going to introduce and differentiate central immune tolerance and peripheral immune tolerance. It's important to note that sometimes our adaptive immune response can make a mistake, and it can mistakenly produce what are known as self-reacting T and B cells. Self-reacting here just means that these T and B cells will react to our own healthy, uninfected cells. These self-reacting T and B cells will actually harm our own healthy cells, which is a bad thing. Again, this is a mistake that our adaptive immune system can occasionally make. To prevent this mistake from happening, our body strictly controls T and B cell development to ensure that these self-reacting T and B cells are not produced.

There are two types of tolerance mechanisms that control T and B cell development: central immune tolerance and peripheral immune tolerance. Central immune tolerance occurs via negative selection of mature T and B cells before they leave the primary lymphoid organs. Recall that the primary lymphoid organs include the bone marrow for B cells and the thymus for T cells. This negative selection involves the elimination or removal of self-reacting T and B cells by apoptosis, essentially killing any cell that binds self or harmless antigens. Peripheral immune tolerance, on the other hand, involves the selection of mature T and B cells after leaving the primary lymphoid organs and making their way to the secondary lymphoid organs. Peripheral immune tolerance involves both negative selection as well as positive selection, positively selecting T cells that bind any MHC and negatively selecting T cells that bind harmless antigens.

Positive selection refers to promoting cells that do something, and negative selection refers to inhibiting or killing cells that do something. We'll distinguish that a little bit better down below when we get to this interesting image of Jigsaw from the scary movie Saw. In this context, self-reacting T and B cells will become anergic or unresponsive and will eventually undergo apoptosis, negatively selecting for those T cells that bind harmless antigens. These two tolerance mechanisms are so strict that approximately 95% of all T and B cells that we initially create undergo apoptosis, and only 5% of the T and B cells will make it through these mechanisms. This small percentage of cells that make it through are very effective at doing their job appropriately and targeting harmful antigens.

Now, negative selection, as its name implies, involves something negative: if you do something specific — in this case, if T and B cells bind to harmless and self antigens — then they will die. Positive selection, on the other hand, is somewhat positive: if you do something specific — in this case, bind any MHC — then you get to survive. In the images below focused on T cells, notice that central tolerance occurs before the immune cells leave the primary lymphoid organs like the thymus for T cells, and peripheral tolerance occurs after they reach secondary lymphoid organs like the lymph nodes.

In central tolerance, if T cells bind to harmless or self antigens, they are eliminated via apoptosis. However, if negative selection fails, some self-reacting T cells may not be eliminated and can leave the primary lymphoid organ. These T cells are then exposed to peripheral tolerance mechanisms involving both positive and negative selection. Positive selection promotes cells that sufficiently bind and recognize antigens on MHC, allowing them to survive, while negative selection eliminates those that do not.

Ultimately, of all the T cells produced, only a small percentage can make it through both central and peripheral tolerance mechanisms and generate an immune response. The T cells and B cells that we have in our secondary lymphoid organs are those that have undergone these strict tolerance mechanisms and are capable of generating an appropriate immune response.

This concludes our brief lesson on central versus peripheral tolerance mechanisms. We'll get some practice applying these concepts as we move forward in our course. I'll see you all in our next video.