LYMPHOPOIESIS: CHARACTERISTICS, STAGES, REGULATION - BIOLOGY - 2025

The lymphopoiesis is the process of formation and maturation of the lymphocyte series, including B lymphocytes, T lymphocytes and NK cells. Lymphocytes start from a precursor cell of the lymphocyte lineage called the common lymphoid progenitor.

B lymphocytes are produced and matured in the bone marrow but are activated in the secondary lymphoid organs. Instead, T lymphocytes are produced in the bone marrow, mature in the thymus, and become activated in secondary lymphoid organs.

Lymphopoiesis scheme. Source: Jmarchn Edited image.

For their part, NK lymphocytes are produced in the thymus and from there they go into the peripheral blood. Very little is known about the maturation process of these cells.

During the lymphopoiesis process, cells acquire characteristic membrane receptors. However, it is important to note that in the case of lymphopoiesis, it is not possible to differentiate the different precursors by simple morphology.

The same occurs with mature lymphocytes in peripheral blood, because despite the fact that each type of lymphocytes has a percentage in peripheral blood, it cannot be differentiated between one and the other.

In the case of B lymphocytes, these represent 10-30% of circulating lymphocytes, while the sum of CD4 and CD8 T lymphocytes represents 65 to 75%. Finally, NK lymphocytes are in a proportion of 15-20%.

characteristics

Lymphopoiesis is a complex process, as it has characteristics that make it unique. For example, stem cells originate in the bone marrow but the maturation process can occur in the marrow or in the thymus, depending on the type of lymphocyte.

On the other hand, in other cell lines the various precursors are morphologically recognizable, but in the case of lymphopoiesis this is not the case.

The different precursors of lymphocytes in bone marrow are not distinguishable from each other from the morphological point of view, since when observing a sample of bone marrow all the immature lymphocytic precursors will appear identical.

The same happens with the various types of mature lymphocytes that circulate in the blood (B, T lymphocytes), they all look morphologically similar. Therefore, by simple microscopic observation they cannot be differentiated.

The only exception are NK lymphocytes, which can appear as larger cells with granules in their cytoplasm.

Origin

The hematopoietic process begins with the differentiation of the stem cell. This can give rise to multipotential progenitor cells for any cell lineage (erythroid, granulocytic, lymphoid, monocytic and megakaryocytic).

Next, it will be explained about lymphopoiesis. The multipotential progenitor cell called the lymphoid and myeloid colony forming unit (CFU LM) emerges from the pluripotential stem cell. It can differentiate into two progenitor cells CFU-L (CFU Lymphoid) and CFU-M (CFU-Myeloid).

Lymphocytes come from the multipotential stem cell (CFU-L), also known as PCL (common lymphoid progenitor).

Stages

Lymphopoiesis begins from lymphoid CFU, which will be explained in stages according to the type of lymphocytes. From it, progenitor cells can be generated for each type of lymphocyte, that is, in CFU-B (B lymphocytes), CFU-T (T lymphocytes and NK lymphocytes).

-Formation of B lymphocytes

Bone marrow phase

B lymphocytes start from CFU-B. The ripening process is long. One part occurs within the bone marrow and another stage outside it.

The process goes through several cell types, listed in order below: pre-B cells, pre-B lymphocytes, immature B lymphocytes, mature B lymphocytes, naïve B lymphocytes, immunoblast B lymphocytes, and plasma cells.

As already mentioned, these cells are indistinguishable from each other in terms of their appearance, but they differ molecularly, since as the maturation process progresses, membrane markers called B-cell receptors (BCR) are added.

These membrane receptors are nothing more than IgM and IgD type antibodies that bind to the lymphocyte membrane. All receptors are obtained in the bone marrow.

Extramedullary phase

The lymphocyte that is released into the circulation is the virgin lymphocyte. It is so called because it has never been faced with an antigen and therefore has not reacted to it.

The virgin lymphocyte will travel through the body. The tour includes passages through the secondary lymphoid organs such as the lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT). From there you can return to circulation and so on you can repeat the route, as long as it is not activated.

Now, if during its passage through the secondary lymphoid organ it encounters an antigen, it will cease to be a virgin and will become an immunoblast B lymphocyte, that is, it becomes activated.

To complete the cell activation process, it becomes a functional plasma cell or a memory cell. This occurs within the germinal centers located in the cortex of the secondary lymphoid organs.

The plasma cell or plasmacyte, as it is also known, is capable of making specific antibodies against the antigen that activated it. Immunoblast B lymphocytes and plasma cells exert their function in the lymphoid organ, and it is very unlikely that they will re-enter the circulation.

Plasmacytes are large cells and when these accumulate in the germinal centers it is evidenced by the enlargement of the lymphoid organ involved (splenomegaly, adenomegaly).

-Formation of T lymphocytes

T lymphocytes start from the CFU-T cell. In this case, the process is divided into two stages: the one that occurs within the bone marrow and the one that occurs outside it, specifically in the thymus.

Bone marrow phase

The process in bone marrow is quite short, since the protimocyte, also called pro-lymphocyte, is formed from CFU-T. This leaves the bone marrow and goes to the thymus where the final maturation process will occur.

Phase within the thymus

The protocyte passes into the peripheral blood and reaches the thymus where the maturation process ends. From protimocyte it passes to the following states: immature thymocyte and mature thymocyte. The latter is transformed into virgin T lymphocyte, which enters the peripheral blood.

Maturation process of T lymphocytes in the thymus

The maturation process consists of the acquisition of the T cell membrane receptor known as (TCR) and CD membrane markers (cluster of differentiation). The most important in these cells are CD4 and CD8.

Lymphocytes that have the CD4 receptor are called helper lymphocytes. There are two classes: CD4 T lymphocytes (helpers) and CD4 + CD25 T lymphocytes (suppressors). Note that the latter, in addition to having the CD4 receptor, also possess the CD25.

On the other hand, it is worth mentioning that CD4 helper lymphocytes are divided into two categories or types: Th1 and Th2.

Each has a specific role in the immune system. Th1s direct their attention to stimulating cytotoxic lymphocytes to release lymphokines. While the Th2s are related to the stimulation of plasma cells so that they secrete antibodies.

Finally, the lymphocytes that have the CD8 receptor on their membrane are called cytotoxic.

All lymphocyte precursors are physically identical to each other, therefore they cannot be identified by simple microscopic observation. The same is true of mature T and B lymphocytes circulating in peripheral blood.

Phase out of the thymus

The virgin T lymphocytes will travel through the circulatory system, passing through the secondary lymphoid organs. These can return to the circulation as long as they are not activated in the secondary lymphoid organs. This is repeated over and over again.

When a virgin T cell meets an antigen, it becomes an immunoblast T cell. Later, it becomes a T lymphocyte, an effector that can differentiate into a T helper lymphocyte (TCD4) or also a cytotoxic T lymphocyte (TCD8).

-Formation of NK lymphocytes

The name of the NK lymphocyte comes from the acronym in English (natural killer). There is not much information about this cell. So far it is known that it shares the same initial precursor of T lymphocytes, that is, part of the CFU-T.

An important step in the formation of an NK cell is the loss of the CD34 receptor in its precursors.

One of the differences it has with the rest of the lymphocytes is that its plasma membrane does not have specific receptors. Although it does contain nonspecific receptors such as CD16 and CD57.

That is why this cell acts without the need to activate itself, participating in innate or nonspecific immunity, fulfilling very important functions in immunological surveillance.

Its functions include eliminating cells infected by bacteria or viruses and eliminating cells with malignant characteristics. The elimination is carried out by cell lysis through a substance called perforin.

NK lymphocytes also react against non-self tissues, being responsible for rejections in transplants.

Regulation of lymphopoiesis

The bone marrow microenvironment plays a critical role in maintaining the most undifferentiated progenitor cells.

In the first stage of differentiation of lymphoid cell precursors, interleukin 3 (IL3) intervenes as a stimulating substance.

In the following phases, other interleukins act, such as IL-4, IL-5 and IL-6, which stimulate the proliferation and differentiation of the B lineage.

For its part, IL-1 is involved in the activation process of both T and B lymphocytes.

Likewise, suppressor T lymphocytes help in the homeostasis of the immune response, since they are responsible for releasing lymphokines that inhibit the proliferation of cells of the lymphocyte lineage. These include IL-10 and transforming growth factor β (TGF-β).

It should be borne in mind that after the age of 60 most of the thymus has regressed and therefore the population of mature T lymphocytes will decrease. That is why the elderly are always more susceptible to infections.

Histology

Virgin lymphocytes

Naive lymphocytes are small cells, measuring approximately 6 µm in diameter. They have a scant cytoplasm, with compact chromatin.

It has poorly developed organelles, for example: the endoplasmic reticulum and the Golgi apparatus, while mitochondria are rare.

Lymphoblast or immunoblast T lymphocyte

They are larger than naive cells, measuring approximately 15 µm. The cytoplasm is more abundant, the nuclear chromatin clears, to the point of being able to observe a nucleolus. Organelles that were previously underdeveloped or scarce are now well formed and abundant.

Effector cells

Immunoblast T lymphocytes can transform into effector cells. These are short-lived. They possess well-developed organelles like their precursor.

Memory cells

Memory cells are the size of virgin lymphocytes. They are kept in a state of lethargy or rest for many years.

NK lymphocytes

Unlike the rest of the lymphocytes, this one changes a bit in appearance, appearing as a slightly larger cell and with certain granules in the cytoplasm. It has well developed organelles and more cytoplasm. These features are detectable using electron microscopy.

References

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