What is the lymphocyte activation?

The activation of lymphocytes is the consequence of their interaction with an antigenic pathogen, directly for B lymphocytes and through the molecule of histocompatibility complex for T lymphocytes. Antigens are recognized by different characteristic structures present on their surfaces; 

This activation thus allows the lymphocytes to pass from a naive mature stage to an activated mature stage. They will correspond to the cytotoxic T lymphocytes, helper T lymphocytes, plasma cells, and memory cells. The activation signals will allow the activation of transcription factors and, thus, the expression of new molecules essential to activated mature cells, among other things, for their proliferation.

Activation of T lymphocytes

At the level of T lymphocytes, the antigenic fragment presented by the MHC molecule is recognized by the TCR. It is important to specify that the antigenic fragment recognized by the TCR is necessary for peptide nature.

1. Activation of T-CD4 lymphocytes

2. Recognition of the antigenic fragment

T-CD4 lymphocytes are activated by antigenic fragments presented by MHC-II molecules, themselves expressed by the antigen-presenting cells and more typically by the antigen-presenting cells.

Once present at the level of the secondary lymphoid organs, the antigen-presenting cells will be truly scanned by the naive T-CD4 lymphocytes. It will seek to specifically recognize the antigenic fragment of which they are specific. If the TCR recognizes an antigen, the T lymphocyte will stop, allowing the formation of a particular contact zone, which is called a "synapse."

Following the formation of the synapse, T-CD4 lymphocytes will be activated by two types of signals:

- Stimulation signals allowed by kinases, which Phosphorylation the ITAMs of intracytoplasmic regions of the CD3 chains associated with the TCR.

- Costimulation signals, essential for full activation of lymphocyte, which is induced by the interaction between the clusters of differentiation CD28 present on the surface of the T-CD4 lymphocyte receptor. Moreover, the interaction between the CD40 receptor-ligand (CD40-ligand) present on the surface of the lymphocyte and the CD40 differentiation cluster present on the surface of the antigen-presenting cell.

Differentiation of LT-CD4

Once these cells are activated, there will be a proliferation and differentiation phase. Indeed the destiny of the CD4 cell will be different depending on the cytokines produced by the antigen-presenting cell, which activates it. We thus distinguish:

- The auxiliary T lymphocytes 1 (or LT-H1) obtained due to the interleukins IL-12, IFN-γ, and TNF-β. LT-H1 is also responsible for the increase in expression of the B7 receptor essential for the formation of cytotoxic T lymphocytes.

- The helper T cells 2 (or LT-H2) obtained through the interleukin IL-4. They play a role in the activation of B lymphocytes.

- The helper T lymphocytes 17 (or LT-H17) obtained using interleukin IL-23.

1. Activation of T-CD8 lymphocytes

2. Recognition of the antigenic fragment

T-CD8 lymphocytes are activated by antigenic fragments presented by MHC-I molecules, themselves expressed by nucleated cells of the organism. In fact, the T-CD8 lymphocytes circulate in the pre-cytotoxic state and receive activation signals to become cytotoxic. These signals are given to them following their interaction, also in the form of a "synapse, "with the cell presenting the antigenic fragment associated with MHC-I. As for LT-CD4, there are two types of signals:

It is necessary to specify that most of the target nucleated cells express the MHC-I molecules, which is not the case for the B7 receptor expressed by the antigen-presenting cells. Activation is not direct and requires a second interaction with an antigen-presenting cell, which will mainly be the dendritic cell.

However, the dendritic cell sometimes expresses the B7 receptor too weakly. In this way, depending on the situation we are facing, the T-CD8 lymphocyte can be activated by:

- The infected dendritic cell: The infected dendritic cells present B7 directly and in sufficient quantity. They thus allow the activation of the cytotoxic LT, which will lyse the target cell presenting the antigen. The antigen must be presented by the MHC-I molecules and therefore correspond to antigens synthesized in the cell (viral antigen, etc.).

- The non-infected dendritic cell by cross-priming or cross-presentation: The non-infected dendritic cells require the internalization of the antigen. It will be degraded in the cytoplasm, in order to be presented by MHC-I molecules, although the antigen comes from outside.

- The cross-presentation is based on the fact that the phagosome wall contains constituents of the endoplasmic reticulum (MHC-I, transporters). After internalization, fragments of antigens are released into the cytoplasm through channels. These antigens are degraded by the proteasome and again internalized in the phagosome to associate with class 1 molecules of the MHC.

- The cross-priming is based on the fact that some infectious agents will induce apoptosis in phagocytic cells. Apoptotic micro-particles are thus formed, which will be internalized by dendritic cells.

- The concern of these cells is that it expresses B7 too weakly; this case requires the help of LT-CD4 (LT-H1 in particular). In fact, LT-H1 will recognize the antigens presented by MHC-II molecules expressed on the surface of dendritic cells. This is the interaction between the ligand of the CD40 receptor (CD40-ligand) present on the surface of LT -H1 and the CD40 differentiation cluster present on the surface of dendritic cells, which will induce the increase in expression of B7. This increase in expression of B7 will thus allow the formation of costimulation signals and, therefore, the activation of cytotoxic LT.

Mechanism of action of cytotoxic LT

Cytotoxic T lymphocytes are responsible for cellular immunity resulting in the death of the target cell. There is a release of cytotoxic granules (particular lysosomes) which contain two categories of molecules called cytotoxins:

- The perforin is a protein that by polymerizing forms pores in the membrane of the target cell.

- The purpose of serine-esterases is to destroy DNA by activating caspases, which will fragment the DNA in order to induce apoptosis.

Activation of B lymphocytes

Activation of B lymphocytes can be done in different ways depending on the involvement of T lymphocytes: thymo-dependent or thymo-independent.

1. Thymo-dependent activation

2. Activation signals

Thymo-dependent activation is the most commonly used, and just as for the activation of T lymphocytes. There are two types of signals which are induced by the antigen-BCR interaction:

- The stimulation signals are responsible for the one hand for the internalization. In other words, of the endocytosis, of the antigen-BCR complex, thus allowing the degradation of the antigen in the endosomal system. The peptide fragments obtained will be associated with MHC-II molecules, giving the B lymphocyte the status of an antigen-presenting cell. The stimulation signals are also responsible for the activation of tyrosine kinases. It will phosphorylate the ITAM motifs of the intra-cytoplasmic regions of the dimer Igα-Igβ associated with BCR. Thereby it causes the activation of the transcription factor, which will allow the expression of many molecules.

- The costimulatory signals are essential to total cell activation and are enabled by a number of co-receptors (CD19, CD21, and CD81) that amplify the signal.

Proliferation and increase of affinity

On the other hand, the activated LBs still receive proliferation signals, which this time is not induced by the antigen-BCR interaction but by the LT-H2. These signals will be induced by various means: the interaction between the CD40 receptor-ligand (CD40-ligand) present on the surface of LT-H2. And the CD40 differentiation cluster present on the surface of LB, the IL-4 interleukins produced by LT-H2.

Following this activation, the lymphocytes obtained will multiply intensely, and some of them will give plasma cells. It will then produce, as explained in the previous chapters, IgM of low affinity for the antigen.

The other cells will continue to multiply in the primary follicles in order to form germinal centers; these cells are then called centroblasts. The latter no longer express BCR because mutations take place at the level of the genes coding for the variable parts of the heavy chains and of the light chains.

Hypermutation.

The centroblasts will thus become centrocytes which no longer divide and which re-express on their surface a BCR, which always recognizes the same starting antigen but with a modified affinity. These centrocytes will be selected by antigen-BCR complexes present at the level of follicular dendritic cells, and in this way, only those expressing BCRs having a strong affinity for the antigen will receive the survival signal.

1. The fate of centrocytes

At this stage, the selected centrocytes will again interact with the LT-H2 allowing the formation of two types of cells:

- Plasma that will produce antibodies (IgM) of high affinity for the antigen. The secretion of interleukins will allow class switching, and in this way, there will no longer be secretion of IgM but of IgA, IgE or IgG. There will be a latency of 4 to 8 days between the production of low-affinity immunoglobulins and those of high affinity.

- Memory B cells that will leave the secondary follicles to go in traffic and in order to facilitate the encounter with antigen. These cells have the characteristic of being able to secrete directly, without latency time, high-affinity antibodies during a second infection with the same antigen. The response obtained occurs for much lower levels of antigen and is considerably greater in intensity.

2. Thymo-independent activations

Unlike thymo-dependent activation, thymo-independent activations do not require the help of LT-H2 to produce the antibodies. They are classified into two categories:

- The activation thymus-independent type 1 causes a polyclonal stimulation of B cells. This activation does not pass through the BCR but common to all LB receptors that recognize pathogens that are called mitogens.

- The thymo-independent type 2 activation results in monoclonal stimulation of the B lymphocytes. This activation this time passes through the BCR, which recognizes repetitive sugar determinants. However, essentially an IgM production will be observed.

Author: Vicki Lezama