After introducing all the types of immune cells, we are now ready to get a sense of the overall structure of the immune system. This will mean looking at the lymphatic system. We actually introduced this system in the anatomy and physiology series, in the context of its involvement in the circulatory system, with lymphatic vessels taking in interstitial fluid at capillary beds and returning it to the bloodstream. But the lymphatic system also includes the primary organs and tissues that make up the immune system, so let’s take a deeper look at this system now. Let’s start by discussing why this system is needed. Once again, in the previous tutorial, we discussed how the immune system is made up of billions of individual cells spread throughout the body, which are able to recognize signs of danger and infection. In order to be activated, an immune cell must sense foreign molecules called antigens which are only found on infectious microbes, diseased cells, or other foreign sources. Immune cells also must receive multiple, distinct signals from other cells called co-stimulatory signals. Co-stimulatory signals confirm the presence of a threat, and help prevent trigger-happy immune cells from causing damage in the case of a false alarm. B and T lymphocytes are unique in that each lymphocyte recognizes one, and only one, specific antigen. This specific antigen is called the lymphocyte’s cognate antigen. Remember that B cells produce antibodies that can neutralize infectious microbes, while T cells recognize and kill infected or cancerous self cells. T cells can only recognize their cognate antigen when they are bound to surface proteins on other cells, in a process called antigen presentation. Although B cells can recognize their cognate antigens without help from other cells, many B cells need help from T cells to become fully activated. To do this, they present their antigen to helper T cells that are specific for the same antigen, activating the helper T cell so that the T cell can in turn fully activate the B cell. Although the reliance on other cells for immune activation helps prevent inappropriate immune reactions, this requirement also poses a potential challenge. In a multicellular organism, which can be made up of trillions of cells, how are two specific immune cells supposed to meet and provide each other the stimulation they require in order to carry out their respective roles in defense, and how do they do this quickly enough to protect the body from being overrun with infectious invaders? This is where the lymphatic system comes in. For those of you who missed my other tutorial on this system, here’s a quick summary. Every tissue in the body is bathed in fluid called lymph, which contains cellular waste products, dead cell debris, and potential pathogens. Lymph is pushed through lymphatic vessels into tiny, bean-shaped organs called lymph nodes. Humans have hundreds of lymph nodes deposited all over the body, and these nodes act as strategic outposts where immune cells can mingle and meet, giving each other the activating and costimulatory signals necessary to launch a successful immune attack. Let’s now describe each component of this system in more detail from the perspective of immune activity. First up in the lymph nodes. Each lymph node is surrounded by a protective layer of connective tissue called the capsule. Lymph arrives to the node in afferent lymphatic vessels, and then enters the sinuses, which are channels that allow lymph to flow through the different compartments of the node. Lymph node sinuses are lined with macrophages and dendritic cells that sample lymph for pathogens and debris that could trigger an immune reaction. Macrophages in the sinuses act like flypaper in the lymph node, trapping lymph-borne pathogens and preventing them from infecting other cells in the node. The real power of the lymph nodes in coordinating immune responses comes from their exquisite organization. Each lymph node has specific compartments for distinct cell types, defined largely by chemokines, which allows for lymphocytes to efficiently find their cognate antigens and interact with other cells in ways that will launch an immune response. Closest to the capsule is the outer cortex of the lymph node, or the B cell zone, which is made up of spherical structures called follicles that are full of B cells, as one might guess. As we move deeper into the node, we find the T cell zone, which is full of T cells. Dendritic cells, which have been sampling bits of microbes or cellular debris throughout the body, migrate to the T cell zone of lymph nodes when they become activated. Here, they present these antigens to the T cells in the lymph node, looking for the T cell that matches their antigen. Helper T cells tend to live along the margin between the B and T cell zones, so that they can find the B cell that shares its cognate antigen, and give rise to germinal centers, which are sites of B cell activation and division. Naïve lymphocytes, meaning B and T cells that haven’t been activated yet, drain from the blood into the lymph nodes, where they circulate through their respective zones, engaging in a sort of cellular speed-dating, looking for cells presenting their cognate antigen. If they don’t find it, they move from lymph node to lymph node and eventually circle back to the bloodstream. If they do find it, and receive the proper costimulation, the lymphocyte becomes activated, divides rapidly, and migrates to the site of trouble to fight the threat. Lymph nodes and lymphatic vessels are the main structures comprising the lymphatic system, but they are not the only ones involved in immune organization and defense. Other structures include the spleen, the thymus, and mucosa-associated lymphoid tissues, so let’s talk about these as well. The spleen is the largest lymphatic organ in the body. With a dark reddish-purple color, it sits right behind the stomach and has two main functions. The first is to remove old red blood cells from circulation, which occurs in a region of the spleen called the red pulp, and second, to filter pathogens and immune complexes from the blood, which occurs in regions called the white pulp. Unlike lymph nodes, however, the spleen only filters blood, not lymph. The spleen also holds an important reserve of blood, platelets, and monocytes. The red pulp makes up about 75% of the spleen’s volume, and is comprised of the Cords of Billroth and venous sinus. The Cords of Billroth, or the splenic cords, are lined with connective tissue and fibroblasts. They are also full of macrophages. Splenic blood enters “open circulation” in the cords, meaning the blood is not flowing through endothelial-lined vessels, and here old or damaged red blood cells can be eaten by red pulp macrophages. In order to re-enter circulation, red blood cells must enter the venous sinuses by passing through the interendothelial slit. This slit is a narrow passageway between endothelial cells that only healthy, flexible red blood cells can fit through. Old and damaged blood cells that cannot fit through the slit remain trapped in the red pulp, where they are disposed of by macrophages and dendritic cells. Microbes and infected red blood cells coated in antibodies are also destroyed by macrophages in the red pulp. This process of filtration allows the spleen to remove old blood cells from the circulation, and also enables the recycling of iron from old red blood cells to be used in new ones. Interspersed within the red pulp are pockets of white pulp, which have a similar structure to the lymph nodes, with T cell zones and B cell follicles. In the spleen, the T cell zone surrounds the arterioles and is located in the periarteriolar lymphoid sheath, or PALS. Outside the sheath are the B cell follicles, which are surrounded by the marginal zone, which is where the white pulp meets the red pulp. Macrophages and dendritic cells in the marginal zone can help filter circulating antigens, blood-borne pathogens, and cells or particles coated in antibodies, called antigen-antibody complexes. The marginal zone also contains special noncirculating B cells called marginal zone B cells, which do not require T cell help for activation, and seem to be effective first responders at sensing and neutralizing blood-borne threats that appear at the marginal zone. Next up, the thymus is another important lymphoid organ. Unlike the lymph nodes and the spleen, which enable immune responses by coordinating interactions between lymphocytes and antigen-presenting cells, the thymus is the site of early T cell development. In humans, it is positioned right above the heart, and it is the biggest and most active during infancy and childhood. T cell progenitors migrate from the bone marrow to the thymus, where thymic stromal and epithelial cells guide their development. Like other lymphatic tissues, the thymus has distinct regions, which are called the cortex and the medulla, which correspond to different stages of T cell development. Less mature cells can be found in the cortex, and more mature cells are in the medulla. Once fully developed, naïve T cells leave the thymus to circulate through the bloodstream and lymph nodes. The last lymphatic tissue we will discuss is actually a catch-all term for several different regions of lymphatic tissue, and these are the mucosa-associated lymphoid tissues, or MALT. Mucosal surfaces include the digestive tract, airways, the urogenital tract, salivary glands, lactating breasts, as well as the conjunctivae and lachrymal glands of the eye. MALT can also be found in the tonsils, adenoids, and appendix. Mucosal surfaces are thin and permeable, often lined by just a single layer of epithelial cells. This is critical because mucosal surfaces facilitate interactions with the surroundings. For example, the airway epithelium enables gas exchange, and the intestinal epithelium is essential for nutrient absorption. However, this thin barrier also renders mucosal surfaces particularly susceptible to infection. To counter the increased risk of infection, most mucosal surfaces are equipped with MALT. These are structurally similar to lymph nodes, with B cell follicles and T cell zones, but they have some specialized features depending on the tissue type. For example, gut-associated lymphoid tissue, or GALT, in the intestine is supplied with antigen from special cells called microfold cells, or M cells. M cells continuously sample antigen from the intestinal lumen and transfer it to the Peyer’s patches, which are a type of GALT in the small intestine. M cells in nasal-associated lymphoid tissue and bronchus-associated lymphoid tissue, or NALT and BALT respectively, catch inhaled microbes and microbes trapped in mucus, making them available for digestion and antigen presentation by dendritic cells. Mucosal surfaces are often patrolled by activated lymphocytes, even in the absence of infection. MALT is also uniquely effective at regulating immune responses. Think of all the harmless bacteria, food, and other particles that pass through mucosal surfaces that should not trigger an immune response. Regulatory responses in the mucosa are constantly at play to help prevent constant immune activation in response to these harmless antigens. B cells at mucosal sites often produce a specific class of antibody called IgA that is good at preventing bacteria from crossing the epithelial barrier without inducing an immune response. All of these mechanisms work together to keep the mucosal barrier surfaces resistant to infection without requiring an overactive immune response. And with that we have dramatically expanded our understanding of the lymphatic system and lymphatic tissues. Now that we have the big picture covered, it’s time to zoom back in on immune cells, and learn more about how they communicate.