Lymphocytes Development and Activation
Lymphocytes (B cells and T cells – we’ll not talk about NK cells here) go through a generalizable sequence of maturation events. Each starts in the Bone Marrow (BM) as a Hematopoietic Stem Cell (HSC), where it starts its development. T cells leave the BM relatively sooner and go to the Thymus, while B cells remain in the BM for most of their development and then finalize development in the spleen.
Positive Selection for BCR/TCR Development
Regardless of the type of cell (T or B), development occurs in two stages – First, each cell will attempt to make a unique lymphoid receptor (B cells have a BCR; T cells have a TCR). In order to do this, genetic material must be shuffled. While this shuffling does randomize the binding pocket of the lymphoid receptor, it may also destabilize these same receptors’ structure. To account for this, lymphocytes undergo a ‘positive selection’ period that ensures that a viable receptor is formed. This is actually done twice: once to ensure that a ‘Pre-Lymphoid Receptor’ is formed and again to for a ‘Mature Receptor.’ However, both are considered positive selection. Failure to pass this selection point leads to death of the cell. (In the figure below, Pre-Lymphocyte receptors are colored red, mature receptors are grey)
Negative Selection Against Self-Reactive BCR/ TCRs
Once cells have survived positive selection, they are considered Immature Lymphocytes. Although the terminology is poor here, these immature cells have mature lymphocyte receptors. At this point, these receptors have to be tested against all possible ‘Self ‘- antigens. In this case, binding means that these cells have the potential to react against the self – this is a no, no. The Immune System turned against the self is extraordinarily dangerous. Therefore, self-reactive cells are eliminated during this negative selection process. (In the figure below, mature lymphocytes have grey nucleus, all prior stages have red nuclei).
Following these developmental stages, the cells that have survived both positive and negative selection are 1) stable, mature lymphocyte receptors and 2) not reactive to ‘self’. These cells then enter the immune repertoire for that organism and are available to react against any foreign threats. Again, it is important to emphasize that each lymphocyte has a unique receptor and therefore will only get activated by a unique foreign antigen.
I may write more later to discuss some of the details that distinguish B and T cell development, but for now, this generalizable description will suffice.
Once a part of the immune repertoire, lymphocytes are on the lookout for foreign antigen that is capable of being bound by that cell’s receptor. Depending on the cell type, this interaction may be in one of several contexts (either in the context of MHC I, MHC II or as a naïve, soluble antigen), but regardless of the context, these ‘naïve’ lymphocytes will become activated by binding of their lymphocyte receptor. And once activated, lymphocytes will proliferate and differentiate. Differentiation typically goes in one of two general directions:
1) generating activated effector cells (these secrete antibody if B cells, kill target cells, if CD8 T cells, or become helpers if CD4 T cells)
2) generating memory cells, cells that act the same as the mature naïve cell that was activated, but are more numerous and can, themselves be activated upon stimulation.
An example of this activation is shown below in this HHMI video about how CD8 T cells can be stimulated to activate and then kill any target cells. This video also does a good job of illustrating how antigens get digested within a cell and expressed in the context of MHC I.