Pathways of different antigens to secondary lymphoid tissue

In this article, I briefly describe the pathways of several pathogens or antigens to secondary lymphoid tissue.

Table of Contents

The interaction between the lymphocytes and the antigens

The pathogens and antigens perforate our barrier tissue to start an adaptive immune response by making contact with the naïve T and B lymphocytes. The naïve lymphocytes remain absent in barrier tissue but circulate among lymph nodes and the spleen.

The B cells and T cells will be searching for antigens at different places. The B cells will be searching for unprocessed antigens in the follicle, whereas the T cells will be looking for antigen-MHC complexes on the surface of antigen-presenting cells in the T cell zones. Thus, the antigen appears in two different forms, a whole antigen and one with MHC complexes.

The first PRR signals activate antigen-presenting cells, which process antigen at the infection site. After getting activated, antigen-presenting cells can migrate to local lymph nodes through afferent lymphatic vessels.

Some particulate antigens and pathogens directly travel to the lymph nodes through lymphatic vessels. Some of the unprocessed antigen is scanned by B cells in the follicles. Certain antigen is processed by antigen-presenting cells in lymph nodes and presented with MHC.

The processed antigen enters the T cell zones of secondary lymphoid tissue

An antigen, after its processing enters a lymph node towards the T cells, circulating on the FRC network in the paracortex. The antigen-presenting cells get activated through PRR signaling. This not only enhances their antigen-presenting abilities but also elevates the expression of specific chemokine receptors.

The antigen is processed by activated antigen-presenting cells in barrier tissues. Antigen-presenting cells elevate the chemokine receptor CCR7, which opens the path for other chemokines.

CCL21 is an important cytokine for interacting with the endothelial cells lining the lymphatic vessels. If the CCR7-CCL21 interaction is hindered, then antigen-presenting cells would not be able to move towards the lymph node. Antigen-presenting cells are pushed towards the subcapsular sinus by the lymph flow.

Inside the lymph node, the antigen-presenting cells with the help of the cytokine receptor CCR7, make a way to the paracortex and settle themselves along the FRC conduits. At specific subregions of the paracortex, the naïve CD4⁺ and CD8⁺ T cells are activated by specific subsets of the antigen-presenting cells.

The antigen-presenting cells having the ability to cross-present the antigens are presented by class I MHC molecules. These cells have the best interaction with the naïve CD8⁺ T cells. The naïve CD4⁺ T cells get activated by dendritic cells, including Langerhans cells, which can go to draining lymph nodes from the skin.

B cell zones- The place for unprocessed antigen

Antigen-presenting cells with processed antigens make their way towards the lymph node, whereas unprocessed antigens head towards B-cell zones. T cells are searching for processed antigen-MHC complexes on antigen-presenting cells, but B cells are looking for unprocessed antigens.

An unprocessed antigen can enter a lymph node in many ways depending on its size and solubility. If it is quite small and soluble enough, then the whole antigen can travel to the lymph node through blood. Afferent lymphatics carry larger antigen particles and pathogens to the lymph node.

A specialized group of macrophages residing in the subcapsular sinus of a lymph node captures the antigen opsonized by complement and/or antibody complexes.

These specialized macrophages are also called CD169P⁺ macrophages. These macrophages transfer the antigen to non-antigen specific B cells and other macrophages expressing complement and Fc receptors residing within the lymph node.

Afterward, these B cells and macrophages pass on an antigen to follicular dendritic cells. The follicular dendritic cells have complement receptors of their own and are relentlessly examined by naïve B cells.

Specialized antigen-presenting cells trap blood-borne antigen

The spleen is a part of the lymphatic system. It stores and filters blood and also prepares white blood cells, which give protection from infection. It is composed of red pulp and white pulp separated by the marginal zone. The white pulp is arranged into B-cell follicles and T-cell zones.

The antigen present in the bloodstream is trapped by the spleen and is directly emptied into the marginal zone. In the marginal zone, the innate immune cells respond to the antigens and get them processed.

The activated antigen-presenting cells travel towards the T cell zone of the white pulp, where they are scrutinized by circulating naïve T cells. White pulp is also invaded by whole or particulate antigens directly or through a pathway system involving CD169⁺ macrophages.

Lymphocytes and antigen- The first interaction

Before the onset of infection, B cells in the follicles and T cells in the paracortex (T-cell zone) search for antigens. Dendritic cells keep their presence primarily in the paracortex and also between the follicles.

When an antigen gets an entry into the body, the cells behave accordingly. The activated dendritic cell enters the lymph node from the infection site and travels to the paracortex (zone of T cells). The antigen-specific T cell comes in contact with the dendritic cell after a short period. It engages MHC peptide on the surface of the dendritic cell and gets activated.

Inside the follicles, the antigen-specific B cells attack soluble antigens and get them activated. The activated B cells from the follicles move towards the paracortex, the zone of T-cells.

In the T cell zone, B cells caper along with the antigen-specific T cells, which also have been brought to the border between the T cell zone and the follicle.

An activated B cell acquires several options after it engages with an activated T cell. One of the options includes the return of B cells to the follicle to generate a germinal center.

CD4⁺ T cells slow down their movement after interacting with antigens

The primary and secondary humoral and cellular adaptive immune responses are initiated by CD4⁺ T cells. They are activated by antigen-presenting cells like dendritic cells presenting processed antigens with MHC.

The activated CD4⁺ T cells, after getting signals from dendritic cells, get differentiated into distinct effector helper cells. Some effector cells help differentiate the CD8⁺ T cells, while other effector T cell subsets help the differentiation of activated B cells.

Research on the interaction of live, naïve CD4⁺ T cells in a lymph node shows their agile movement via paracortex before interaction with antigen. However, after getting attached to MHC-peptide complexes, their movement slows down. They are also known as the arrested T cells, which can form both transient and stable interactions with dendritic cells.

The B cells present at the border between the follicles and lymph node paracortex need succor from CD4⁺ T cells

The naïve B cells, when traveling through the follicles, come in contact with antigens and are partially activated. When they get engaged with an activated helper T cell, they get ligands that stimulate CD40 signaling. This stimulation releases cytokines that promote B-cell differentiation and the formation of memory. Each helper T cell, a subset like T_H1, and T_H2 encourages B cells to produce varieties of antibody isotypes for different pathogens.

After binding antigen through their B cell receptor, B cells get activated. Then, after a few hours, they move in the follicle towards the T-cell zone. Before encountering an antigen, B cells express CCR4 and CCR7, the chemokine receptors. Thus, they get attracted to the chemokines present in the follicle.

Correspondingly, CCR5, a chemokine receptor is expressed by activated helper T cells, which take them towards the chemokines made in the follicle. In this way, the movement of both B cells and T cells towards the border between the follicle and paracortex, helps in the interaction between them and to get help from each other.

The long interaction between B cells and T cells creates an immunologic synapse, where clustered TCR, CD40L, and CD28 molecules engage with B cell’s class-II MHC peptide, CD40, and CD80/86 molecules respectively.

The B cells differentiate and proliferate with the help of cytokines delivered by the T cells into the synaptic space. The activated B cells then travel to the outer edges of the follicle. Some activated B cells directly differentiate into IgM-secreting plasma cells. These cells exit the lymph node, whereas others return to the follicle interior, sowing a germinal center. Here, they undergo proliferation multiple times.

Conclusion

Different antigens have different pathways to secondary lymphoid tissues. In the barrier tissues, the activated antigen-presenting cells process antigens. The antigens, after processing head towards the lymph node, whereas unprocessed antigens head towards the B cells.

Before the onset of infection, the B cells search for antigens in the follicles, whereas the T cells search for antigens in the paracortex. The dendritic cells can search for antigens in both the follicles and the paracortex.

The naïve CD4⁺ T cells show their quick movement through the paracortex. However, after attaching to the peptide-MHC complex, they slow their movement and become arrested T cells.

B cells, when engaged with an activated helper T cell, start differentiating to produce memory cells.