The picture described thus far has a fatal flaw: receptors that are randomly generated and subject to random changes from hypermutation, could easily bind to self and initiate autoimmune responses (responses where the immune system attacks the body). However, autoimmune responses are relatively rare; generally the immune system is tolerant of self, i.e. it does not attack self.
How does the immune system ensure tolerance?Figure 8. T-cells are centrally tolerized via clonal deletion in the thymus.
Tolerance is implemented via another class of lymphocytes, called helper T-cells, because they mature in the thymus, and "help" B-cells. The thymus is an organ located just behind the breastbone. Most self proteins are circulated through the thymus, so any T-cells maturing in the thymus are exposed to most self proteins. If a maturing T-cell binds to any of these proteins, it will be censored, or removed, in a process that is called clonal deletion (see figure 8). T-cells that survive the maturing process and leave the thymus will be tolerant of most self proteins. This is essentially centralized tolerance, because the immature T-cells are tolerized in a single location.
Ensuring tolerance of B-cells is a much harder problem, because there is no single location in which affinity maturation takes place. Recall that during affinity maturation B-cells hypermutate, so even if the parent B-cells were tolerant of self, they can clone daughter B-cells that are self-reactive. Affinity maturation takes place in the lymph nodes, of which there are many distributed throughout the body. What is needed is some mechanism for distributed censoring.
How is distributed censoring done in the immune system?Figure 9. Costimulation from helper T-cells implements distributed censoring for B-cells.
Helper T-cells provide distributed censoring of B-cells through a mechanism known as costimulation. To be actived, a B-cell must receive costimultion in the form of two disparate signals: signal one occurs when the number of pathogens binding to a B-cell's receptors exceeds the affinity threshold; signal two is provided by helper T-cells. A helper T-cell will only provide signal two to a B-cell if it recognizes the pathogen that the B-cell has captured.
How does a T-cell recognize pathogens captured by B-cells?
B-cells ingest the pathogens that they capture, and break them up into protein fragments, or peptides, which they present to the helper T-cells. If the helper T-cells recognize the peptides presented by the B-cells, they will costimulate the B-cell by providing signal two; if signal two is not provided, the B-cell will die. Because T-cells undergo centralized tolerization in the thymus, most helper T-cells are self tolerant, and so will not costimulate a B-cell that recognizes self.
The specialization of the different lymphocytes gives the immune system the ability to provide a fast adaptive response that is not self-reactive. T-cells have the responsibility for self-tolerance, thus freeing B-cells to hypermutate and adapt to a specific pathogen. The more specific the B-cells are, the more efficiently they can capture pathogens, and the more rapidly they can eliminate the infection.