Cytotoxic T Lymphocytes and Mucosal Surfaces
The lymphatic system houses large populations of immune cells which are released upon detection of a pathogen.
Describe the features of the lymphatic system as they relate to the immune response
- The lymphatic system contains lymph: a fluid that bathes tissues and organs and contains white blood cells (not red blood cells).
- Once B and T cells mature, the majority of them enter the lymphatic system, where they are stored in lymph nodes until needed.
- Lymph nodes also store dendritic cells and macrophages; as antigens are filtered through the lymphatic system, these cells collect them so as to present them to B and T cells.
- The spleen, which is to blood what lymph nodes are to lymph, filters foreign substances and antibody -complexed pathogens from the blood.
- lymph: a colorless, watery, bodily fluid carried by the lymphatic system, consisting mainly of white blood cells
Lymph, the watery fluid that bathes tissues and organs, contains protective white blood cells, but does not contain erythrocytes (red blood cells). Lymph moves about the body through the lymphatic system, which is made up of vessels, lymph ducts, lymph glands, and organs such as tonsils, adenoids, thymus, and spleen. Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites that are known as lymph nodes.
The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which include monocytes (the precursor of macrophages) and lymphocytes. Most cells in the blood are red blood cells. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).
Recall that cells of the immune system originate from stem cells in the bone marrow. B cell maturation occurs in the bone marrow, whereas progenitor cells migrate from the bone marrow and develop and mature into naïve T cells in the organ called the thymus. On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body house large populations of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens as it drains from tissues. These antigens are filtered through lymph nodes before the lymph is returned to circulation. Antigen-presenting cells (APCs) in the lymph nodes capture and process antigens, informing nearby lymphocytes about potential pathogens.
The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. The spleen is also the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, which filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.
Classes of T Cells
T cells play a central role in cell-mediated immune response through the use of the surface T cell receptor to recognize peptide antigens.
Distinguish between: naive, effector (helper and cytotoxic), memory and regulatory T cells
- T cell progenitors are derived from the bone marrow but travel to the thymus where they mature.
- T cells can be divided into three main subtypes: effector, memory, and regulatory cells. Each type performs a distinct function during an immune response to foreign antigens.
- T cells subtypes are differentiated by the expression of unique cell surface markers, such as CD4 for helper T cells and CD8 for cytolytic or cytotoxic T cells.
- cytotoxic: of, relating to, or being a cytotoxin
- cytolytic: Of or pertaining to cytolysis
Cellular immunity is mediated by T lymphocytes, also called T cells. Their name refers to the organ from which they’re produced: the thymus. This type of immunity promotes the destruction of microbes residing in phagocytes, or the killing of infected cells to eliminate reservoirs of infection. T cells do not produce antibody molecules. They have antigen receptors that are structurally related to antibodies. These structures help recognize antigens only in the form of peptides displayed on the surface of antigen-presenting cells.
T cells consist of functionally distinct populations. These include naive T cells that recognize antigens and are activated in peripheral lymphoid organs. This activation results in the expansion of the antigen-specific lymphocyte pool and the differentiation of these cells into effector and memory cells. Effector cells include helper T cells, and cytolytic or cytotoxic T cells. In response to antigenic stimulation, helper T cells (characterized by the expression of CD4 marker on their surface) secrete proteins called cytokines, whose function is to stimulate the proliferation and differentiation of the T cells themselves, as well as other cells, including B cells, macrophages, and other leukocytes. Cytolytic or cytotoxic T cells (characterized by the expression of CD8 marker on their surface) kill cells that produce foreign antigens, such as cells infected by viruses and other intracellular microbes.
Memory T cells are an expanded population of T cells specific for antigens that can respond rapidly to subsequent encounter with that antigen and differentiate into effector cell to eliminate the antigen. Another class of T cells called regulatory T cells function to inhibit immune response and resolve inflammation. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction.
Cell-mediated immunity involves cytotoxic T cells recognizing infected cells and bringing about their destruction.
Summarize the cell-mediated immune response
- Once a pathogen enters a cell, it can no longer be detected by the humoral immune response; instead, the cell-mediated immune response must take over to kill the infected cell before it can allow the virus or bacteria to replicate and spread.
- T cells recognize infected cells by interacting with antigen present on their MHC II molecules; before a T cell can do so, it must be activated via interaction with an antigen presenting cell, or APC.
- Once a cytotoxic T cell (TC) is activated, it will clone itself, producing many TC cells with the correct receptors; some portion of the cells are active and will help destroy infected cells, while others are inactive memory cells that will create more active TC cells if the infection returns.
- Helper T cells (TH cells) also aid in cell-mediated immunity by releasing signaling molecules known as cytokines which can recruit natural killer cells and phagocytes to destroy infected cells and further activate TC cells; they do not directly destroy pathogens.
- cytotoxic T cell: a subgroup of lymphocytes (white blood cells) that are capable of inducing death to infected somatic or tumor cells; part of cell-mediated immunity
- cytokine: any of various small regulatory proteins that regulate the cells of the immune system; they are released upon binding of PRRs to PAMPS
Just as the humoral immune response has B cells which mediate its response, the cellular immune response has T cells, which recognize infected cells and destroy them before the pathogen inside can replicate and spread to infect other cells. Unlike B cells, T lymphocytes (T cells) are unable to recognize pathogens without assistance. First, an antigen-presenting cell (APC, such as a dendritic cell or a macrophage ) detects, engulfs (via phagocytosis in the case of macrophages or by entry of the pathogen of its own accord in the case of dendritic cells), and digests pathogens into hundreds or thousands of antigen fragments. These fragments are then transported to the surface of the APC, where they are presented on proteins known as Major Histocompatibility Complexes class II (MHC II, see ). T cells become activated towards a certain antigen once they encounter it displayed on an MHC II. After a virus or bacteria enters a cell, it can no longer be detected by the humoral immune response. Instead, the cellular immune response must take over. To do so, a T cell will become activated by interacting with an antigen of the infecting cell or virus presented on the MHC II of an APC.
Cytotoxic T cells mediate one arm of the cellular immune response
There are two main types of T cells: helper T lymphocytes (TH) and the cytotoxic T lymphocytes (TC). The TH lymphocytes function indirectly to tell other immune cells about potential pathogens, while cytotoxic T cells (TC) are the key component of the cell-mediated part of the adaptive immune system which attacks and destroys infected cells. TC cells are particularly important in protecting against viral infections because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the TC creates a large clone of cells with one specific set of cell-surface receptors, similar to the proliferation of activated B cells. As with B cells, the clone includes active TC cells and inactive memory TC cells. The resulting active TC cells then identify infected host cells.
TC cells attempt to identify and destroy infected cells by triggering apoptosis (programmed cell death) before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. To recognize which cells to pursue, TC recognize antigens presented on MHC I complexes, which are present on all nucleated cells. MHC I complexes display a current readout of intracellular proteins inside a cell and will present pathogen antigens if the pathogen is present in the cell. TC cells also support NK lymphocytes to destroy early cancers.
Cytokines released by TH cells recruit NK cells and phagocytes
Cytokines are signaling molecules secreted by a TH cell in response to a pathogen-infected cell; they stimulate natural killer cells and phagocytes such as macrophages. Phagocytes will then engulf infected cells and destroy them. Cytokines are also involved in stimulating TC cells, enhancing their ability to identify and destroy infected cells and tumors. A summary of how the humoral and cell-mediated immune responses are activated appears in. B plasma cells and TC cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.
Regulatory T Cells
Regulatory T cells are a subset of T cells which modulate the immune system and keep immune reactions in check.
Describe the function and types of regulatory T cells
- Regulatory T cells (Tregs) are critical to the maintenance of immune cell homeostasis as evidenced by the consequences of genetic or physical ablation of the Treg population.
- Tregs are classified into natural or induced Tregs; natural Tregs are CD4+CD25+ T-cells which develop, and emigrate from the thymus to perform their key role in immune homeostasis.
- Adaptive Tregs are non-regulatory CD4+ T-cells which acquire CD25 (IL-2R alpha) expression outside of the thymus and are typically induced by inflammation and disease processes, such as autoimmunity and cancer.
- autoimmunity: The condition where one’s immune system attacks one’s own tissues, i.e., an autoimmune disorder.
Regulatory T cells are a component of the immune system that suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions and chronic inflammation. Regulatory T cells come in many forms, with the most well-understood being those that express CD4, CD25, and Foxp3. These cells are also called CD4+CD25+ regulatory T cells, or Tregs. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.
CD4+Foxp3+ regulatory T cells have been called “naturally-occurring” regulatory T cells, to distinguish them from “suppressor” T cell populations that are generated in vitro. Additional suppressor T cell populations include Tr1, Th3, CD8+CD28–, and Qa-1 restricted T cells. The contribution of these populations to self- tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for CD4+CD25+ T cells as well as recent studies showing evidence for FOXP3 in CD4+CD25- T cells.
An additional regulatory T cell subset, induced regulatory T cells, are also needed for tolerance and suppression. Induced Regulatory T (iTreg) cells (CD4+CD25+Foxp3+) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. iTreg cells develop from mature CD4+ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses. Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable Foxp3 expression and wider demethylation.
T Cell Receptors
The T Cell Receptor (TCR) found on the surface of T cells is responsible for recognizing antigens.
Discuss the role of the T cell receptor (TCR)
- Many TCRs recognize the same antigen and many antigens are recognized by the same TCR.
- The TCR is composed of two different protein chains (that is, it is a heterodimer). In 95% of T cells, this consists of an alpha (α) and beta (β) chain, whereas in 5% of T cells this consists of gamma and delta (γ/δ) chains.
- When the TCR engages with antigen and MHC, the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co- receptors, specialized accessory molecules, and activated or released transcription factors.
- polymorphic: relating to polymorphism (any sense), able to have several shapes or forms
- major histocompatibility complex: MHC is a cell surface molecule that mediate interactions of immune cells with other leukocytes or body cells. MHC determines compatibility of donors for organ transplants as well as one’s susceptibility to an autoimmune disease. In humans, MHC is also called human leukocyte antigen (HLA).
T lymphocytes have a dual specificity: they recognize polymorphic residues of self major histocompatibility complex (MHC) molecules, which accounts for their MHC restriction; they also recognize residues of peptide antigens displayed by these MHC molecules, which is responsible for their specificity. MHC molecules and peptides form complexes on the surface of antigen presenting cells (APCs). The receptor that recognizes these peptide-MHC complexes is called the T Cell Receptor (TCR). Clones of T cells with different specificities express different TCRs.
The biochemical signals that are triggered in T cells following antigen recognition are transduced not by the TCR itself, but by invariant proteins (CD3, and zeta), which are non-covalently linked to the antigen receptor to form the TCR complex. T cells also express other membrane receptors that do not recognize antigens but participate in responses to antigens; these are collectively called ‘accessory molecules’. The physiologic role of some accessory molecules is to deliver signals to the T cells that function in concert with signals from the TCR complex to fully activate the cell.
The antigen receptor of MHC-restricted CD4 helper T cells and CD8 cytolytic T cell is a heterodimer consisting of two transmembrane polypeptide chains, designated alpha and beta, covalently linked to each other by disulfide bonds. Each alpha and beta chain consists of one variable domain (V), one constant domain (C), a hydrophobic transmembrane region, and a short cytoplasmic region. The V regions of the TCR contain short stretches of amino acids where the variability between different TCRs is concentrated, and these form the hypervariable or complementarity-determining regions (CDRs). The recognition of peptide-MHC complexes is mediated by CDRs formed by both the alpha and beta chains of the TCR.
Adaptive Immunity and the Immunoglobulin Superfamily
Adaptive immunity is stimulated by exposure to infectious agents and recruits elements of the immunoglobulin superfamily.
Describe the role of immunoglobulins in the adaptive immune response, specifically in humoral immunity
- The concept of adaptive immunity suggests de novo generation in each individual of extremely large repertoires of diversified receptors and selective expansion of receptors that match the antigen /pathogen.
- Adaptive immune receptors of T and B lymphoid cells belong to the immunoglobulin superfamily and are created by rearrangement of gene segments.
- Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies.
- cytokine: Any of various small regulatory proteins that regulate the cells of the immune system.
Precision of Immunoglobulin
Adaptive immunity is stimulated by exposure to infectious agents and increases in magnitude and defensive capabilities with each successive exposure to a particular microbe. The defining characteristics of adaptive immunity are specificity for distinct molecules and an ability to “remember” and respond more vigorously to repeated exposures to the same microbe.
The components of adaptive immunity are lymphocytes and their products. There are two types of adaptive immune responses: humoral immunity and cell-mediated immunity. These are driven by different elements of the immune system and function to eliminate different types of microbes. Protective immunity against a microbe may be induced by the host ‘s response to the microbe or by the transfer of antibodies or lymphocytes specific for the microbe. Antibodies or Immunoglobulins bind antigens in the recognition phase and the effector phase of humoral immunity.
The Immunoglobulin Superfamily
Immunoglobulins are produced in a membrane -bound form by B lymphocytes. These membrane molecules function as B cell receptors for antigens. The interaction of antigens with membrane antibodies on naive B cells initiates B cell activation. These activated B cells produce a soluble form of immunoglobulin that triggers effector mechanisms to eliminate antigens.
These antibodies are part of a larger family called the immunoglobulin superfamily. The immunoglobulin superfamily (IgSF) is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on structural features shared with immunoglobulins, which are also known as antibodies. They all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors, and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules, certain cytokine receptors, and intracellular muscle proteins. They are commonly associated with roles in the immune system.