CD4 T LYMPHOCYTES: STRUCTURE, FUNCTIONS, MATURATION - BIOLOGY - 2025

The CD4 T cells are a type of T lymphocyte having cell functions primarily as "accessory" or "partner" for the specific immune response or adaptive. They are characterized by the presence of a membrane receptor known as the "T cell receptor complex", abbreviated as TCR (T Cell Receptor). However, there are different subpopulations of T cells that are identified by the presence of other membrane marker molecules.

These molecules are protein in nature and are known as part of a "group of differentiation" or CD (Cluster of Differentiation). Accordingly, T cells can be divided into two main groups: CD4 T lymphocytes and CD8 T lymphocytes.

Representation of the CD4 coreceptor on a T helper lymphocyte during its activation mediated by an antigen presenting cell (APC) (Source: Xermani via Wikimedia Commons)

The latter are also known as "cytotoxic T cells" since, in the humoral immune response, they directly intervene in the elimination of cells invaded by viruses or intracellular microorganisms.

CD4 T lymphocytes are popularly known in the literature as “helper T lymphocytes”, since they participate in the activation of other lymphocytes of the immune system: B lymphocytes. Their participation promotes both the activation and the production and secretion of antibodies.

Structure

CD4 T cells share the structural characteristics of every other cell of the lymphoid lineage. They have a prominent nucleus, which confines the cytosol to a narrow ring between its plasma membrane and the nucleus.

They don't have too many internal organelles, but on electron micrographs they looked alike some mitochondria, a small Golgi complex, free ribosomes, and a few lysosomes.

These cells originate in the bone marrow from a common precursor with other lymphoid cells such as B cells and “natural killer” (NK) cells, as well as the rest of the hematopoietic cells.

However, their maturation and activation occurs outside the bone marrow, in an organ known as the thymus, and they can exert their functions in some secondary lymphoid organs such as the tonsils, the appendix and others.

They are distinguished from other cells of the lymphoid lineage by the expression of specific markers, specifically the "T cell receptor" (T Cell Receptor). These surface proteins can be viewed as protein complexes that function primarily in the recognition of antigens presented to them.

Associated with these proteins is another protein complex known as CD3, which is required for the signaling that takes place during antigen recognition.

On the other hand, helper T lymphocytes express on their surface a type of “marker” molecule known as CD4 that, like all the molecules of the differentiation groups, recognize specific sites of the receptors “restricted” by the MHC molecules of class II.

Types of CD4 T Lymphocytes

Different names can be found in the literature for the different types of T lymphocytes with CD4-type markers, but a type of nomenclature stands out that discriminates the type of cytokine that these cells are capable of producing.

In this way, several classes of helper T lymphocytes have been defined, among which the TH1, TH2, TH9, TH17, TH22, THF and Tregs or regulatory lymphocytes stand out.

TH1 lymphocytes secrete interferon gamma (IFN-γ), a useful cytokine for the activation of other cells of the immune system known as macrophages. Type 2 helper lymphocytes (TH2) secrete a wide variety of interleukins that promote antibody production.

Follicular helper T lymphocytes or THFs, found in lymphoid follicles, are involved in the activation of B cells and also "assist" in the production and secretion of antibodies by secreting abundant amounts of cytokines.

Another class of helper lymphocytes, the regulatory T lymphocytes or Tregs, regulate a large number of cellular functions through cell-cell contacts, the expression of surface molecules, and the enhancement of the response to different growth factors.

With regard to the development of these "subsets" of CD4 T lymphocytes, different studies have shown that they are derived from the same T cell precursor, that is, they do not originate from separate lineages that are compromised prior to antigenic stimulation.

On the contrary, the differentiation of each type of helper lymphocyte is influenced by many of the microenvironmental aspects to which the precursor cell is subjected, which is believed to be a naive, mature CD4 T lymphocyte, is stimulated by cytokines produced by macrophages.

Features

CD4 T lymphocytes function primarily as helper cells. These are cells that are activated and generate immune responses against infections once they find, recognize and interact with an invading antigen.

Their ability to recognize and bind foreign antigens is considerably different from that of B cells, since the latter are capable of recognizing soluble antigens in their "naive state" condition, before their complete differentiation.

In contrast, T lymphocytes (in general) can only recognize peptide antigens attached to other molecules encoded by the genes of a protein family known as "Major Histocompatibility Complex" or MHC (Major Histocompatibility Complex) and this is called " restriction by MHC ”.

There are at least three classes of MHC proteins and CD4 T cells recognize antigens presented in the context of MHC class II.

They are called T helper cells or "helpers" because they "help" the B cells that are characterized by the production of T-dependent antibodies, that is, they need the presence of T lymphocytes.

Its fundamental responsibility lies in the production of soluble cytokines that participate in different immunological processes.

As immune memory cells

A certain set of differentiated, mature CD4 T cells can live for longer periods of time and provide a faster response when the organism in which they are found faces the same antigen a second time.

These cells that are dedicated to "remembering" the antigens that activated them and triggered their differentiation are known as "memory T cells".

Maturation and activation

CD4 T lymphocytes originate in the bone marrow and subsequently migrate to the thymus to differentiate and mature. The progenitor lymphoid cells of the T lymphocytes present in the thymus are known as "thymocytes."

Thymocytes go through different stages of maturation, in which the membrane markers that characterize them are gradually expressed (previous reference was made to the TCR and CD3 markers).

Activation process of a T lymphocyte (Source: DO11.10 via Wikimedia Commons)

During the maturation process, helper T cells that recognize foreign antigens are selected and those that recognize molecules of the organism that give rise to them are eliminated. This is a very important protection mechanism against the presence of "self-reactive" cells.

How does activation happen?

Inactive T lymphocytes are in a period of mitotic senescence or, what is the same, they are not actively dividing and are arrested in the G0 phase of the cell cycle.

Some “accessory” cells known as antigen presenting cells or APC (Antigen Presenting Cells) participate in the activation process. These cells have the function of "presenting" antigens bound to MHC class II proteins that are selectively recognized by TCRs on the membrane of CD4 T lymphocytes.

During this process, which takes place in the thymus, the lymphocytes differentiate into lymphoblasts, changing in shape and size. Lymphoblasts can divide and proliferate, multiplying the number of cells in the population.

The interaction between the TCR receptor (on the surface of the CD4 T cell) and the antigen bound to MHC class II (on the surface of the APC cell) forms a complex that ensures specific recognition.

Once the presented antigen is recognized in the context of MHC class II, both the CD4 lymphocyte and the APC cell begin to secrete cytokines that contribute to lymphocyte activation.

When the lymphocyte is activated it multiplies, forming new identical cells, specific for the antigen in question and which is in a "naive" or "naïve" state, which is not modified until they meet the antigen for which they were "designed. ”.

Programmed cell death

The human body, like that of many mammals, has the capacity to produce hundreds of lymphocytic cells in very short periods of time.

In addition, since the differentiation of a T cell involves the random rearrangement of the genes that code for the recognition proteins of the antigens that are presented to it, there are hundreds of different populations of cells capable of recognizing different "parts" of the same antigen. or different antigens.

This multitude of cells implies certain physiological dangers, since some of the patterns recognized by the membrane receptors of T cells could coincide with the patterns of some self-molecules.

Additionally, not all these cells are destined to carry out their functions immediately, since they require interaction with the defined antigen.

Thus, lymphocyte "homeostasis" is achieved in the primary lymphoid organs, triggering the programmed cell death pathways in those cells that are not necessary or that do not differentiate and fully mature.

References

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2. Actor, JK (2014). Introductory Immunology Basic Concepts for Interdisciplinary Applications. London: Academic Press.
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4. Cavanagh, M. (nd). T-cell activation. British Society for Immunology.
5. Reinherz, E., Haynes, B., Nadles, L., & Bernstein, I. (1986). Leukocyte Typing II. Human T Lymphocytes (Vol. 1). Springer.
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