Figure 2. Differentiation and interaction of T and B lymphocytes. MHC is the major histocompatibility complex.
The stem cells that give rise to T lymphocytes reside within the bone marrow (Fig 2) and enter the blood circulation as immuno-incompetent cells (i.e., not responsive to antigen). They home to the outer region (cortex) of the thymus where they undergo clonal expansion and differentiation in response to endocrine secretions produced by the thymus. During this process, T lymphocytes that recognize “self-antigens” as foreign antigens are destroyed by apoptosis. T lymphocytes that do not recognize “self” as foreign leave the cortex to enter the medulla were they are further processed into mature T lymphocytes. Mature T lymphocytes exit the thymus by the post-capillary venules located at the cortex-medulla boundary.
Mature T lymphocytes can be classified by function as:
(1) Helper T cells (TH) initiate antigen response(s) by activating B lymphocytes.
(2) Killer T cells (TC) directly contact infected cells causing cell death.
(3) Regulatory T cells (TREG) regulate the magnitude and duration of the immune response.
The mature T cells leave the thymus entering the circulating population of lymphocytes in the blood. About 80-90% of lymphocytes in the circulation are T cells. The T lymphocytes home to diffuse lymphatic tissues where they mediate discrimination between “self” and “non-self” in both cellular and humoral immune responses (Fig 2).
T lymphocyte mediated cellular immune functions encompass:
(1) Removal of neoplastic cells
(2) Rejection of transplanted organs or tissue
(3) Mediation of certain autoimmune diseases
(4) Recovery from intracellular microbial and viral infections
The B lymphocytes attain immunological maturity independent of the thymus (Fig 2). In birds, some stem cells reach immuno-competence in a lymphatic mass called the Bursa of Fabricius. In humans, there are no organs directly corresponding to the bursa. Instead, B-lineage cells within the fetal liver and bone marrow and in the adult bone marrow differentiate directly to become immunocompetent B lymphocytes. The B lymphocytes are produced continuously throughout life, their growth and maturation takes a few days. During their maturation, considerable genetic recombination occurs within the immunoglobulin genes to generate a wide variety of antigen-binding specificity. The antigen receptor on the surface of B cells is the resulting antibody. There is a single type of antigen receptor for each B lymphocyte.
About 10 to 20% of lymphocytes in the blood circulation are B cells. B cells home to nodules of lymphatic tissue.
B lymphocytes mediate humoral immunity. In most cases, the B lymphocytes need the help of an antigen presenting cell (APC) and/or TH lymphocyte to elicit a response (Fig 2). Once activated, the B cell undergoes clonal division to generate daughter cells, some of which differentiate into plasma cells while others remain as memory B cells (Fig 2). The plasma cells secrete soluble antibodies that match the specificity of the original immunoglobulin-receptor expressed on the B cell surface. This is called the humoral immune response because the antibodies are secreted into the blood for delivery.
Five different classes of immunoglobulins (antibodies) can be made:
(1) IgG constitutes most (~75%) of serum immunoglobulin.
(2) IgA is in colostrum, saliva, tears, and in secretions from nasal, bronchial, vaginal and prostatic tissue.
(3) IgM is important in early immune responses.
(4) IgE is secreted by plasma cells but attaches to mast cells and basophils where it serves as a receptor for allergens.
(5) IgD serves as a receptor for antigens on the surface of B cells and has been implicated in enhancing local and systemic surveillance against air-borne pathogens but its function(s) is not well understood.
Once stimulated, T and B lymphocytes undergo clonal division. This process produces effector cells and memory cells. The increased number of memory (T and B) lymphocytes is an important aspect of acquired immunity because it permits a more robust and rapid response to the antigen with a second challenge (exposure). The secondary immune response is the basis for acquired immunity from vaccines and of hypersensitivity (Nat Rev Immunol 2009, 9:153).
Antigen presenting cells (APCs)
Antigen presenting cells (APCs) include macrophages, Langerhans cells (skin), and subsets of dendritic cells. These cells migrate from the bone marrow to peripheral tissues where they act as sentinels for foreign antigens. When APCs encounter pathogens, they ingest the foreign substances, degrade them into small antigens (called epitopes, e.g., short peptides and polysaccharides) and then display these small antigens on their cell surfaces loaded onto the major histocompatibility complex (MHC). These mature antigen-bearing APCs migrate to lymphatic tissues where they instruct and/or regulate the activation of T or B lymphocytes.
Lymphocytes in lymphatic tissue and organs are supported by a connective tissue stroma that is of mesodermal origin. The stroma consists of reticular cells which secrete extracellular reticular fibers (collagen type III). The reticular cells also direct small lymphocytes (B and T) to specific regions within the lymphatic tissue by exhibiting “address labels” on their cell surfaces. There is one exception: in the thymus, the stromal cells are derived from endoderm and have endocrine functions.
Lymphatic tissue is classified in terms of the relative densities of lymphocyte aggregates as either diffuse (loose aggregates) or nodules (highly organized aggregates). A nodule often contains a light staining central region called the germinal center. Germinal centers are areas of active lymphocyte proliferation and differentiation. Located within the germinal center are the follicular dendritic cells. The follicular dendritic cells secrete cytokines to promote clonal division of the B lymphocytes. They can bind antigen-antibody complexes to their cell surfaces but unlike APCs, the follicular dendritic cells do not process the bound antigen and instead present the intact antigen without the MHC complex. If the nodule has a germinal center, then it is called a secondary nodule. The darker staining periphery of the secondary nodule (called mantle) contains small, non-responding B lymphocytes. Lymphatic nodules can be found nearly anywhere in the body, but they are especially common in the gastrointestinal and respiratory tracts (called Mucosa Associated Lymphatic Tissue, MALT).
Organs of the lymphatic system are divided into two categories:
Primary lymphatic organs in which T and B lymphocytes differentiate from precursor stem cells to immuno-competent cells independent of antigens. These include the thymus (T cells) and bone marrow (B cells) in the adult.
Secondary lymphatic organs are seeded with immuno-competent lymphocytes. These
include lymph nodes, Peyer’s patches, tonsils, and spleen. These organs respond to antigen
and are the principle source of continuing lymphocyte production and function in the adult.
Primary lymphatic organ: Thymus
The thymus is a bi-lobed organ located in the thorax just above the heart. Like all compact organs, a thin, connective tissue capsule surrounds the stroma and parenchyma (Fig. 3). Each lobe is subdivided into partial lobules by connective tissue septa (walls) that carry blood vessels in from the capsule.
The stroma consists of an epithelium formed by stellate-shaped cells called epithelial reticular cells. These cells are attached to each other by desmosomes and have an intracellular system of tonofilaments (intermediate filaments) for support. There are no extracellular connective tissue fibers. The epithelial reticular cells are endodermal in origin. These cells secrete hormones (e.g., thymosin) critical for the maturation and proliferation of immunocompetent T lymphocytes.
The parenchyma of the thymus is separated into a peripheral cortex and a central medulla. The cortex is composed primarily of small T lymphocytes actively dividing and differentiating. The medulla is lighter in appearance since there are fewer lymphocytes but more epithelial reticular cells in this region. Also seen scattered throughout the medulla are unique structures of epithelial reticular cells layered concentrically upon one another in swirls. These structures are called thymic corpuscles or Hassall’s corpuscles. Their function has been identified (Nature 2005) to be endocrine. They secrete lymphopoietin, a hormone critical for differentiation of T cell subclasses. Dendritic cells, macrophages and mast cells are present in the medulla as well.
Figure 3. Diagram depicts the cellular organization of the thymus.
The thymus does not have a hilus. Instead small arteries penetrate the capsule and then follow the interlobular septa into the interior of the organ as arterioles. At the cortex-medulla boundary, arterioles give off capillaries which enter either the cortex or the medulla. Within the cortex and medulla, these capillaries anastomose extensively and then return to the cortex-medulla boundary where they drain into venules. The capillaries are continuous, sealed with tight junctions, and are surrounded by phagocytic epithelial reticular cells to ensure no leakage of antigen. This is known as the blood-thymus barrier.
The blood-thymus barrier is essential for the exclusion of non-self (foreign) antigens from the thymus so that proper selection of immunocompetent T lymphocytes can occur. If a foreign antigen gains access to the thymic cortex, then T lymphocytes capable of recognizing this antigen as foreign would be destroyed.
There are no afferent lymphatic vessels in the thymus. Immature T lymphocytes enter the parenchyma from the blood at the post capillary venules located at the cortex-medulla boundary. The immunocompetent T lymphocytes exit the organ by these same venules (Sci. 328:1129, 2010). Because B cells and foreign antigens do not enter the thymus parenchyma, there are no nodules and no germinal centers. The thymus does not participate in immune reactions.
At puberty, the thymus begins to involute in response to adrenocorticosteroids (steroid hormones secreted by the adrenals) and gonadal steroids. The lymphocyte population declines within the cortex and is replaced by adipose tissue. Hassall’s corpuscles in the medulla enlarge and increase in number. Despite post-pubertal involution of the thymic cortex, the thymus remains a functional organ well into adulthood. However, age-related T-cell mediated immunodeficiency can develop. Interestingly, the subset of naïve TC lymphocytes diminishes with age resulting in the elderly being more susceptible to severe infections.
Failure of T cell mediated immunity may have one of several etiologies. A few examples are:
(1) Severe Combined Immune Deficiency (SCID) can arise from the absence of either bone marrow stem cells or of immuno-incompetent T lymphocytes. The clinical spectrum is broad. Patients are at risk for fungal and viral infections (defective cell mediated immunity) and for bacterial infections (defective humoral immunity). The first known cause of SCID has been shown to be a deficiency in adenosine deaminase (ADA). In patients that lack a matched bone marrow donor, enzyme replacement (PEG-ADA) and gene therapy are used.
(2) In Acquired Immune Deficiency (AIDS), the HVTL III virus destroys the mature TH cells. These patients develop severe immune deficiency and are at risk for viral, fungal and bacterial infections.
(3) In Autoimmune diseases, such as Grave’s disease, myasthenia gravis, systemic lupus erythematosus, and rheumatoid arthritis, there is a failure of self-tolerance. The clinical manifestations are diverse and dependent on the antigen involved.