The adaptive immune system is the body’s main line of defence against ever-evolving pathogens. Read on to find where the cells of the adaptive immune system reside and what their mechanisms of action are.


T Cell Receptor complexed with MHC I and II


Primary Immune Response

When antigen exposure occurs for the first time (priming dose), our body gives the primary immune response. There is a latent period wherein immediately after the priming dose, no antibodies are detected in the serum. This is followed by a log phase in which active biosynthesis of antibodies takes place.

During the plateau or steady state, the serum concentration of antibodies remains constant. Finally, a decline phase is observed during which catabolism is greater than synthesis. Thus, the primary response is slow, sluggish and short-living. It has a long lag phase of 5 to 7 days. Low titres of antibodies (IgM) are persistent for short duration.

Secondary Immune Response

A secondary immune response is seen when the same antigen enters the body for a second time (i.e. booster dose). It can be seen after weeks, months or even years. Following a booster dose,  there is a markedly enhanced response characterized by an accelerated appearance of immunocompetent cells and antibodies.

It has a very short and negligible latent phase of 2 to 3 days and high level of antibodies (IgG) lasting for a long period. Thus, the secondary response is prompt, powerful with a prolonged anamnestic or recall response.

Lymphoid Organs

Lymphoid organs are divided into primary and secondary depending on their functions. Primary lymphoid organs include the thymus, bursa of fabricius, bone marrow and intestinal epithelium wherein there is antigen independent proliferation and differentiation of lymphocytes.

Secondary lymphoid organs include lymph nodes, spleen and mucosa associated lymphoid tissue wherein antigenic stimuli initiate immune responses in lymphocytes. These are tactically positioned so that foreign antigens that enter through bloodstream, peripheral tissues and mucosal sites are skillfully trapped.

The structure of the secondary lymphoid tissues is such that it helps in the initiation of adaptive responses. This is because of better interactions between dendritic cells that bear the antigen, the B cells and T cells.

However, routes of antigen transport, trafficking of lymphocytes and distinctive cell populations decide the task of a specific secondary lymphoid tissue during immune responses to different foreign antigens (including transplanted organs).

Thymus

Location Structure and Histology of the Thymus

Image: “The thymus lies above the heart. The trabeculae and lobules, including the darkly staining cortex and the lighter staining medulla of each lobule, are clearly visible in the light micrograph of the thymus of a newborn. LM × 100. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)” by OpenStax College in Anatomy of the Lymphatic and Immune Systems at https://legacy.cnx.org/content/m46563/1.4/, License: CC BY 3.0

This lymphoepithelial bilobed structure is located behind the upper part of sternum. It acquires a characteristic lymphoid appearance by the 3rd month of gestation and increases in size during fetal development, reaches maximum size at birth, gradually decreases in size with age and finally atrophies.

It is made of lobules, which are differentiated into an outer cortex and inner medulla. The immature lymphocytes from yolk sac, fetal liver and bone marrow travel to the thymus. Within the cortex of thymus, they undergo changes such as maturation and attainment of specific surface characteristics. Further, they move into the medulla of thymus. In the medulla, lymphocytes complete their maturation process and exit into the blood.

Mature T-cells are further seeded into secondary lymphoid organs. It is a major site for lymphocyte proliferation and production of T-lymphocytes wherein lymphocytes acquire new surface antigens.

Thymus confers immunological competence to lymphocytes by hormone-like humoral factors thymosin, thymopoetin etc (which are secreted by thymic epithelium), so that lymphocytes become capable of mounting CMI.

Spleen

Red and white pulp in the spleen

Image: “Red and white pulp in the spleen.” by DooFi. Licence: Public Domain

The spleen is the largest lymphovascular organ having red and white pulp separated by a marginal zone. White pulp is rich in lymphoid tissue while the red pulp is abundant in sinuses and contains large quantities of RBCs.

White pulp is composed primarily of T-lymphocytes. The external lymphoid area is B cell dependent area i.e. germinal centre/mantle layer. Approximately 30 – 40 % of the cells in spleen are T-cells and 50% are B-cells.

Periarterial lymphoid collections in white pulp are known as Malphigian corpuscles or follicles. Following antigenic stimulation, germinal centres are produced in white pulp that are composed of large numbers of rapidly dividing cells. Spleen is the only lymphatic organ specialised to filter blood (in the form of dendritic cells and macrophages). It is a major site for antibody synthesis against blood borne pathogens.

MALT

MALT is the potentially important collection of lymphocytes mainly producing IgA present throughout the mucosal lining of the alimentary, respiratory, genitourinary and other surfaces as isolated cells or small cell clusters.

Such lymphoid tissues of gut are called gut-associated lymphoid tissue (GALT) and those in respiratory tract are called bronchus-associated lymphoid tissue (BALT). Main GALT structures in humans are: tonsils, appendix, Peyer’s patches and the lamina propria of the intestine.

MALT contains a mixture of B cells, T cells, phagocytic cells and APCs. Secretory IgA is the main Ig produced by MALT. IgG, IgM and IgE are also produced locally. It mainly provides immunity against pathogens invading local tissues.

Memory B cells and plasma cells together make up the immunological memory. Both these cells are part of the humoral immune system and are mainly produced in the germinal centres (GCs).

High affinity Abs are produced in the GCs as a result of an amalgamation of the following processes – clonal expansion of B-cells, somatic hypermutation and selection based upon affinity. Cytokine interleukin factor (IL-21) has been recently recognized as a key factor that can directly influence the B cell fate by modulating these processes within GCs. There are various types of immune cells which are involved in the GC B cell responses.

GCs arise 7–10 days post preliminary exposure to thymus-dependent antigen. B cells that are activated undergo intense proliferation throughout first stage of GC formation. A well-marked dark zone is formed by proliferating B cells (centroblasts) in the GC.

Over a period of time, centroblasts mature into centrocytes that migrate into the region containing follicular dendritic cells i.e. light zone of GCs. Within the light zone Ag-Ab complexes are present and the centrocytes thus come in contact with the Ags.

B- and T-Cell Activation

t cell activation

Image: “The T lymphocyte activation pathway is triggered when a T cell encounters its cognate antigen, coupled to a MHC molecule, on the surface of an infected cell or a phagocyte.” Derivative work by Hazmat2. License: Public Domain

Igs present on the B cell surface behave as specific receptors for antigens. When an antigen enters our body, it reacts with the B cells of appropriate specificity. This interaction stimulates B cells to undergo blastoid transformation, converting them into plasma plasts (clone formation) and finally into plasma cells.

Each B cell possesses genetic instructions to produce an antibody of unique antigen specificity as a membrane receptor. Once the signal is received, B cells are differentiated into plasma cells, which produce and secrete antibodies.

An antigen present over MHC molecules leads to the activation of T lymphocyte. The role of various co-stimulatory molecules is to bring about the proliferation and differentiation of T-lymphocytes. APCs assist the co-stimulatory molecules in this task. Only protein antigens loaded over MHC molecule are recognized by T cells.

Contact sensitivity reactions are the reactions wherein there is induction of T-lymphocytes by chemicals that gain entry into our body through the skin. After antigen sensitization, an effectual immune response is produced by the differentiated effector T-cells.

Co-stimulatory Molecules

Differentiation of T Cells Within the Thymus

Image: “Thymocytes enter the thymus and go through a series of developmental stages that ensures both function and tolerance before they leave and become functional components of the adaptive immune response.” by Heather Ketchum, Eric Bright on cnx.org (Download for free at http://cnx.org/contents/a7fa09d4-b7d6-4ae8-a6fa-71037b392af9@1.), License: CC BY 4.0

Co-stimulatory molecules are generated from naive T cells by their proliferation and differentiation into effector cells. APCs help them in this transition. Co-stimulation is vital for an effective immune response presented by T-lymphocytes that are antigen sensitized.

Co-stimulatory molecules that are well known are B7-1(CD80) and B7-2(CD86). There is an expression of co-stimulatory molecules on APCs that are activated. Their ligands, known as CD28, are present on the T-cell surface.

Activated T cells also express CD40 ligands that bind with CD40 occuring on APCs. A cascade follows during activation of the T-cells. The binding of CD40L and CD40 leads to expression of co-stimulatory molecules (B7-1 and B7-2) which further bind to TCR (CD28). Additionally, there is stimulation of T-lymphocyte proliferation and differentiation by cytokines (IL-12) secreted by APCs.

Activation of mitogen activated protein (MAP) is essential for activation of T-cells that is brought about by CD28. Expression of antiapoptotic Bcl-x, and Bcl-2 is stimulated by MAP kinase that causes prolonged cell survival. CTLA-4 (cytotoxic T lymphocyte antigen-4) and PD1 (Programmed Death 1) are inhibitors of CD28 that cause modulation of T-lymphocyte activation. Access to co-stimulatory molecules is totally inhibited when CTLA-4 is activated as it has high affinity for those molecules.

B lymphocytes that are newly formed in the bone marrow migrate to the periphery to be stimulated or excluded from immune system. On activation, B cells will proliferate into clones of cells, some of which form effector cells secreting Igs at a higher rate while others form a long term memory cell.

Thus, part of the immune system represents a one way differentiation pathway, the end point of which is a plasma cell. This is unique in the sense that clonal specificity relevant for a given antigenic epitope regulates the amplification of a given B cell clone. This is the basis of the clonal selection theory proposed by Jerne 1955 and Burnet 1957.

According to this theory, Ig molecules are present on the surfaces of B cells as specific receptors for specific antigens. When an Ag is introduced, it combines with that Ig molecule on the surface which is a complementary fit for it. This interaction results in proliferation of that lymphocyte to form a clone of cells producing an antibody of the same specificity as that on the surface of the parent lymphocyte. Some of the progeny cells are converted into memory cells. Hence, an Ag selects a specific B cell and stimulates it to proliferate into a clone of cells producing specific antibody.

The function of TFH cells: A subset of naive T cells in the T cell zone are activated by antigen and migrate to the follicles where they differentiate into TFH cells which interact with and instruct Follicular B (Fo B) cells to undergo isotype switching, somatic hypermutation, and rapid cellular division to seed germinal centers (GC). Within these germinal centers, TFH cells continue to provide help to GC B cells to facilitate their production of high affinity antibody producing plasma cells (PC) and long-lived memory (Mem) B cells.

Image: “The function of TFH cells: A subset of naive T cells in the T cell zone are activated by antigen and migrate to the follicles where they differentiate into TFH cells which interact with and instruct Follicular B (Fo B) cells to undergo isotype switching, somatic hypermutation, and rapid cellular division to seed germinal centers (GC). Within these germinal centers, TFH cells continue to provide help to GC B cells to facilitate their production of high affinity antibody producing plasma cells (PC) and long-lived memory (Mem) B cells.” by Science boy83. License: CC BY-SA 3.0

Germinal centres (GC) are a place where the important steps of B cell differentiation occur. The steps in B cell differentiation include affinity maturation, class switching, plasma B cells and memory cells formation. Of these events, the GCs are significant for the first two events while the remainder take place outside the GCs too.

E2A, EBF and Pax5 are transcription factors that influence the differentiation of B cells from pleuripotent hematopoetic cells. They help in development of B cells by transcribing certain genes and bringing about their recombination. Development of B-cells takes place in the following order: pleuripotent hematopoetic stem cells – Pro B cells – follicle B cells – marginal B cells – B1 B cells.

Post selection of B cells, there is a differentiation into plasma and memory cells. Usually there is a lack of detectable membrane-bound immunoglobulin in plasma cells. Because of this lack of membrane bound Ig in plasma cells, there is synthesis of secreted antibodies.

These are synthesized at a very high rate of about 1000 Ig molecules per cell per second. Plasma cells are formed from the mature B cells because of an alteration in the processing of RNA. Memory cells are formed from the B cells that are not selected in the light zone of GCs. As a result of class switching, the naive B cells co-express IgM and IgD only, while all Igs are expressed by memory cells.

Dendritic cells (DC) are a type of APCs. They have the capacity to prime T lymphocyte responses. They have to travel all the way to secondary lymphoid organs for presentation of foreign Ags to naive T cells.

This migration of DCs is a multi-step process that is closely regulated. Chemokines play a significant role in this process. Related chemokine receptors are expressed after their production.

TLR (Toll like receptor) is a chemokine that stimulates DC migration. For the process of migration, specific selectin molecules on high endothelial valves are expressed and the stimulated lymph nodes also undergo physical changes. Whenever DCs are activated, the chemokine response is lessened which helps in their migration towards the draining lymph nodes.

DCs are capable of not only Ag processing but also acquiring the Ag. They indirectly lead to naive T lymphocyte activation by expression of co-stimulatory molecules. DCs can pass on specific information to T cells. Depending on the information passed on, the result could be the formation of Th1, Th2, Th17 effectors and memory cells.

Common lymphoid progenitor cells are generated from pleuripotent hematopoetic cells. Transcriptional factors play a major role in the formation of NKCs or Pro-T cells from the common lymphoid progenitor cells.

There is a notch receptor that is activated by lymphoid progenitor cells. On cleavage, the notch receptor travels to the nucleus. This leads to activation of GATA 3, which is a transcription factor that generates Pro-T cells. IL 7 is produced by both the bone marrow as well as the thymus and is an important influence for differentiation of Pro-T cells.

Lymphocyte Activation

Two independent signals are required by lymphocytes for complete activation. A preliminary antigen-specific signal is sent through antigen receptors: T cell receptor (TCR) on T cells or surface Ig on B cells.

A second signal is known as co-stimulation that is independent of the antigen receptor and is imperative for complete activation. It also assists in sustainance of cell proliferation, prevention of anergy and/or apoptosis, induction of differentiation to effector and memory status and allows cell-cell cooperation. Regulation of co-stimulation is in turn done by expression of inhibitory receptors after lymphocyte activation.

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