Acquired immunity is mediated by cells called lymphocytes. Two populations of lymphocytes are found in the body: B lymphocytes (responsible for humoral immunity), and T lymphocytes (responsible for cell-mediated immunity). Most B and T lymphocytes in the body are in a partially differentiated "resting" stage. However, when they encounter an antigenic stimulus they proliferate and are transformed into cells capable of eliminating the antigen source.

1. Components of Acquired Immunity
   1. Humoral Immunity - Immunity that is provided by a family of soluble proteins called immunoglobulins - also called antibodies. These molecules are the principal defense against extracellular organisms such as bacteria and their secreted toxins. They are also effective against viruses before they seek refuge inside cells.

      Antibodies are synthesized by plasma cells which develop from activated B lymphocytes. B Lymphocytes mature and differentiate in the bone marrow. They are distinguished from other lymphocytes by the presence of immunoglobulin molecules that serve as antigen receptors. Each B lymphocyte has its own unique cell-surface immunoglobulin receptor capable of recognizing a specific antigen.

   2. Cell-mediated Immunity - Immunity provided by specialized lymphocytes called T lymphocytes which mature and differentiate in the thymus. Cell-mediated immunity is the principal defense against intracellular organisms such as viruses.

      T lymphocytes are distinguished from B Lymphocytes by the presence of specialized (non-immunoglobulin) cell-surface proteins called T Cell Receptors (TCR's). Each T lymphocyte has a unique TCR capable of recognizing a specific antigen.

      When activated, some T lymphocytes differentiate into Cytotoxic T Lymphocytes (CTL's) which can seek out and destroy infected host cells. Others, known as Helper T Lymphocytes (60% of all T lymphocytes), secrete substances called cytokines - messenger molecules that help coordinate the immune response. CTL's are distinguished from Helper T Lymphocytes by the presence of another cell-surface marker called CD8. Helper T Lymphocytes have their own unique marker called CD4.

   An important functional distinction between humoral and cell mediated immunity is that the former specializes in recognizing free or soluble antigen, while the latter can only recognize antigen that is bound to a cell surface protein known as the major histocompatibility complex (see below).

2. Anatomy of the Immune System - Anatomically, the immune system consists of those specialized tissues that contain T and B Lymphocytes, as well as cells that specialize in recognizing antigens. The cells of the immune system continually monitor the internal and surface environment of the body looking for microbes and other foreign substances.
   1. Lymph Nodes - Provide immune surveillance of tissues. Antigens are carried from various tissues to lymph nodes by the lymphatic system.

   2. Spleen - Those highly vascular organ provides immune surveillance of blood. The bone marrow probably also plays a role in the immune surveillance of blood.

   3. Mucosal Associated Lymphoid Tissue (MALT) - Subepithelial clusters of lymphoid tissue in the respiratory, alimentary, and GU tracts (e.g., Waldeyer's ring of the nasopharynx - tonsils and adenoids - and Peyer's patches in the gut). Provides immune surveillance of mucosal surfaces.

   Lymph nodes, the spleen, and mucosal associated lymphoid tissue are the sites of antigen recognition by lymphocytes, and where the humoral and cell mediated immune response is activated.

   The bone marrow and thymus are the sites of lymphocyte development and maturation. Because of that, they are referred to as primary lymphoid organs. A few immune cells are also located in the dermis, liver, lungs, kidneys and CNS. They help provide immune surveillance of these organs.

   Macrophages and phagocytic cells in the skin called dendritic cells play an important role as antigen presenting cells to Lymphocytes. When tissue macrophages and dendritic cells encounter a foreign antigen anywhere in the body, they take up the antigen, degrade it, and convert it into a form that can be displayed on their cell surface. These cells then migrate to lymph nodes or other lymphatic organs where they "present" the antigen to lymphocytes. This is an important step in the activation of humoral and cell-mediated immunity.

3. General Characteristics of Humoral and Cell-mediated Immunity: While humoral and cell-mediated immunity provide different defensive functions, they nevertheless have several important characteristics in common - antigenic specificity, diversity of antigen recognition, memory, and immune self-tolerance.
   1. Specificity - T and B Lymphocytes are able to recognize and distinguish between different antigens because of specific receptors on their plasma membranes - immunoglobulin receptors on B lymphocytes, T Cell Receptors on T lymphocytes.

      Lymphocyte receptors are protein molecules that have three-dimensional structures complementary to those of specific antigen molecules on microorganisms or other foreign invaders. Lymphocyte receptors and their target antigens fit together much like a key in a lock, or a hand in a glove. Each individual T and B lymphocyte in the body has a unique receptor that allows it to generate an immune response against a specific antigen. For example, a lymphocyte capable of responding to a particular Staphylococcal antigen will only be activated by that organism, and no other. Other microorganisms, with their own unique antigens, are targeted by other lymphocytes.

   2. Diversity - The body has a large repertoire of T and B Lymphocytes, each one with their own unique specificity, and each capable of directing a response against a particular antigen. Because our environment contains a large number of potential pathogens, this diversity allows the immune system to protect us from a wide range of organisms. It has been estimated that the lymphocytes of the immune system can discriminate between more than 10⁷ distinct antigenic structures.

      Amazingly, lymphocytes capable of recognizing all of these potential antigens, are present in the body at birth - prior to any exposure to antigen. Throughout life they lie in ambush, waiting for foreign antigens to invade the body. When an antigen enters the body, it encounters lymphocytes bearing receptors that bind it. Those specific lymphocytes are then "activated" and transformed into a cells capable of eliminating the antigen. Since the specificity of immunoglobulins and TCR's in individual lymphocytes is determined at random, there is a high probability that several of the millions of lymphocytes in the body will be able to recognize a particular antigen - even if the body has never previously been exposed to it.

   3. Memory - When lymphocytes are exposed to a particular antigen for the first time, the resulting immune response is relatively weak and short-lived. This is referred to as the primary immune response. However, repeat exposures to the same antigen characteristically produce a faster, greater, and more sustained immune response - the secondary immune response. This enhanced immune reaction to previously encountered antigens is due to the existence of specialized long-lived T and B Lymphocytes called memory lymphocytes.

      The recognition of antigen by naive "virgin" lymphocytes stimulate the cells to divide and proliferate. Some of the resulting daughter lymphocytes differentiate into active antigen eliminating cells. They only live for a few days - just long enough to rid the body of the invading microorganism. Other activated lymphocytes differentiate into memory lymphocytes that live for months or even years. If these memory cells again encounter the same antigen, they can divide faster and produce greater numbers of antigen eliminating cells than a naive lymphocyte could.

   4. Immunologic Self-Tolerance - Lymphocytes are able to recognize and target many foreign antigens; however, they normally ignore those antigenic substances present on the body's own cells. In other words, the immune system can distinguish between self and non-self.

      Immunologic self-tolerance is thought to develop early in embryonic life as lymphocytes are maturing and differentiating. Those lymphocytes that possess membrane receptors capable of recognizing the body's own antigenic structures are destroyed or inactivated. On the other hand, lymphocytes capable of recognizing foreign (non-self) antigens are permitted to proliferate and populate the lymphatic tissues of the body. This "education" of maturing B and T lymphocytes also continues throughout life.

      • Mechanism of B Lymphocyte Tolerance - The development of antigen specificity by lymphocytes is a random event resulting from the chance rearrangements of immunoglobulin genes (see below). Because of this, it is quite likely that maturing B Lymphocytes occasionally synthesize immunoglobulin receptors that recognize peptide antigens present on the body's own cells. Fortunately, any immature B Lymphocytes capable of recognizing self-antigen are either destroyed or rendered inactive before they can be released into the circulation. Only B Lymphocytes that have immunoglobulin receptors for non- self antigens continue to mature and differentiate normally.

      • T Lymphocyte Tolerance and the Major Histocompatibility Complex (MHC) - All cells in the body have a set of protein receptors on their surfaces that are unique to every individual. Collectively, these complex structures are known as the Major Histocompatibility Complex (also called Human Leukocyte Antigens - HLA's). As their name suggests, they were first recognized as being responsible for the rejection of transplanted organs.

        The normal function of MHC's is to bind peptide fragments derived from the intracellular degradation of microorganisms (as well as from self-proteins) and display them on the cell's surface so they can be specifically recognized by T Lymphocytes. The T Lymphocytes of the body continually scan the surface of cells, ignoring those expressing MHC + self-antigen, but targeting those that display MHC in association with non- self antigens.

        During T Lymphocyte maturation in the thymus, those immature T Lymphocytes that have developed T Cell Receptors capable of locking in on MHC + self-antigen are eliminated from the body before they can mature further. Only T Lymphocytes that recognize MHC + non-self antigens mature into functionally competent immune cells.

   5. More on the Major Histocompatibility Complex

      • Inheritance of MHC's - We all inherit six MHC genes from each parent (labeled A, B, C, DP, DQ, DR) all of which are codominantly expressed. Unlike most genes, MHC genes are polymorphic and have numerous alleles. Because of this, there are millions of possible MHC combinations. The cells of every person have their own unique MHC pattern - analogous to a fingerprint. There is only a one in four chance that siblings will share exactly the same MHC alleles. The chances of matching MHC's exactly with an individual in the general population chosen at random is very remote.

      • MHC's and organ transplant rejection - Our immune system does not normally respond to cells bearing self MHC's unless they are associated with foreign antigens. However, transplanted organs have non-self MHC's stimulate an immune response, causing T Lymphocytes to attack them as though they were invading microorganisms. For this reason, the cells of organ transplant donors must be tested to make sure their MHC's closely match the cells of the recipient or organ rejection will occur.

      • MHC's and disease - MHC's play a role in determining the immune responsiveness of individuals. The inheritance of certain MHC alleles are known to be associated with "hyper-responsiveness" of the immune system and the development of autoimmune diseases. For example 90% of people with ankylosing spondylitis have the MHC allele HLA-B27. 80% of individuals with Type I insulin dependent diabetes mellitus have HLA-DR3 or HLA-DR4.

      • Distribution of MHC's in the body - The MHC's occurring on cells are divided into two major groups: Class I MHC's (the A, B, and C alleles) are widely distributed on most cells of the body. Class I MHC's help activate CD8 positive Cytotoxic T Lymphocytes. Class II MHC's (the DP, DQ, DR alleles), on the other hand are found only on a few cells - mainly antigen-presenting cells such as macrophages and B Lymphocytes. They help to activate CD4 positive Helper T Lymphocytes.

Humoral Immunity

The Humoral Immune Response can be divided into three distinct phases: antigen recognition, lymphocyte activation, and antigen elimination.

1. Antigen Recognition by B Lymphocytes - Before B Lymphocytes can mount an immune response they must first bind their specific antigen. While some B lymphocytes are probably capable of recognizing free antigen, most bind antigen that has been presented to them by macrophages and dendritic cells. This interaction takes place mainly in lymph nodes, spleen, and mucosal lymph tissues.

2. Activation of B Lymphocytes - This involves transformation of resting B Lymphocytes to antibody secreting plasma cells and memory B Lymphocytes. The activation of B Lymphocytes requires two signals: antigen recognition plus stimulation by special lymphocyte hormones called cytokines secreted by Helper T Lymphocytes.
   1. The binding of antigen to specific membrane-bound immunoglobulin on resting B Lymphocytes is the initial trigger for humoral immunity. The antigen-receptor complex is then enveloped by the plasma membrane and transported inside the B lymphocyte where it is enzymatically degraded into peptide fragments. These are then transported back to the surface of the B Lymphocyte where they are re-expressed in association with the B Lymphocyte's Class II Major Histocompatibility Complex.

   2. The B Lymphocyte, with its cell-surface antigen-MHC complex, then comes into contact with Helper T Lymphocytes that have also been activated by the same antigen. The activated Helper T Lymphocytes secrete cytokines which trigger a complex cascade of intracellular biochemical reactions cause the B lymphocyte to divide and proliferate. During several cycles of cell division, some of the daughter cells of the activated B Lymphocytes mature and differentiate into plasma cells - the antigen elimination cells of humoral immunity. Other daughter cells from the activated B Lymphocyte become memory B lymphocytes capable of responding to future stimulation by that antigen.

3. Antigen Elimination Phase - The antigen elimination cell of humoral immunity is the plasma cell which synthesizes and secretes antibodies (immunoglobulins) specific for the antigen that stimulated the humoral response.
   1. Structure of Antibodies Figure 4 - In their un-folded form, the smallest of the immunoglobulins are roughly "Y" shaped molecules composed of four polypeptide chains held together by disulfide bonds. Two of the chains each contain approximately 440 amino acids and are called heavy chains. The two shorter chains, each containing about 220 amino acids, are called light chains. Light chains exist in two forms, designated kappa and lambda. There are five classes of heavy chains designated alpha, gamma, mu, delta, and epsilon. They determine the class of a particular antibody - i.e., whether it is IgA, IgG, IgM, IgD, or IgE. (see below) A complete immunoglobulin molecule is composed of one pair of identical heavy chains, plus one pair of identical light chains - either kappa or lambda - never both in the same antibody.

      Each of the four polypeptide chains are subdivided into distinct functional domains called variable and constant regions:

      • The variable regions of each heavy and light chain are the antigen recognition and binding sites of the antibody. Variable regions have amino acid sequences that vary from one antibody to another. This gives this portion of the antibody a unique three-dimensional conformation allowing it to recognize a specific antigenic structure.

      • The constant regions of immunoglobulin molecules do not display variability in amino acid sequencing. They tend to be same regardless of the antigen specificity of the antibody. The constant region of each immunoglobulin determines the mechanism the body will use to eliminate bound antigen. (See Biologic Effects of Antigen-Antibody Binding below)

      Again, the variable region of the immunoglobulin molecule is responsible for antigen recognition, and the constant region is responsible for the biologic activity of the antibody.

      How do B Lymphocytes produce antibodies with different specificities? Like all proteins, immunoglobulin light and heavy chains are synthesized from mRNA that has been transcribed from a gene. However, unlike most other cellular proteins which are associated with their own unique gene, the very large number of different specific immunoglobulins are synthesized from only three large "master" genes located on chromosomes 2, 14, and 22. Each of these large genes is divided into hundreds of functional segments less than a thousand nucleotide pairs long.

      As a B Lymphocyte matures, the genes coding for heavy and light chains undergo a process of rearrangement where some immunoglobulin gene segments (introns) are randomly selected for permanent excision - leaving a smaller number of segments (exons) to be assembled into the variable and constant coding regions of the gene. The resulting mRNA is derived from only 3-4 segments out of the hundreds of segments that were originally in the "master" genes and serves as the template for the synthesis of a specific antibody.

      Each individual B Lymphocyte synthesizes one type of heavy chain, and one type of light chain (kappa or lambda) - each with their own unique variable region. Mature B lymphocytes assemble the heavy and light chains into a complete immunoglobulin molecule which is expressed on its plasma membrane as an antigen recognition receptor. When that same B Lymphocyte differentiates into a plasma cell, it will secrete immunoglobulin with the same antigenic specificity. Since gene rearrangement is a random process, each B Lymphocyte has its own unique antigen specificity. With several hundred gene segments in each "master" heavy chain and light chain gene, over 10⁷ different combinations are possible.

   2. Classes of Immunoglobulins - There are five different classes of immunoglobulins, each with its own physical and biologic characteristics. As noted earlier, the designation of each class of immunoglobulin is based on its heavy chain structure - IgG antibodies contain gamma heavy chains, IgM contains mu heavy chains, etc. During the course of a humoral immune response a plasma cell can change from one class of antibody to another (e.g., from IgM to IgG) to vary its antigen elimination mechanism. This process is called class switching.

      
      

      Classes of Immunoglobulins
      	IgM	IgG	IgA	IgE
      Mol. Wt.	900,000	150,000	300,000	200,000
      Plasma Concentration	6% of total immunoglobulins	Most abundant immunoglobulin (80% of total immunoglobulins)	13% of total immunoglobulins	Least abundant immunoglobulin - 0.002% of total immunoglobulin
      Crosses Placenta	NO	YES	NO	NO
      Functions	The surface immunoglobulin receptors of B Lymphocytes are IgM. IgM is produced early in immune response (primary response). Particularly effective in the agglutination of microorganisms which facilitates their engulfment by phagocytic cells. IgM is a potent activator of complement leading to the formation of membrane attack complexes and lysis of microorganisms.	The major antibody of the secondary immune response. Activates complement, neutralizes and inactivates bacterial toxins and snake venom, serves as an opsonin to enhance phagocytosis of microorganisms. IgG antibodies coat viruses and prevent their entry into host cells. Some IgG antibodies bind to the flagella or cilia of microorganisms, immobilizing them, and preventing their spread in tissue.	Present in mucous secretions. Inhibits adherence of microorganisms to the surface of mucous secreting cells thereby preventing entry into body across mucosal surfaces.	IgE has a high affinity for mast cells and basophils. Mast cell-bound IgE + ANTIGEN triggers release of vasoactive and chemotactic agents from these cells. IgE is responsible for hypersensitivity reactions such as anaphylaxis, asthma, hayfever, etc. It also plays a role in providing protection from parasites such as helminths.

      
      

      Clinical usefulness of antibody classes: Measuring the relative concentration of IgM vs IgG in the plasma is useful for determining whether an infection is acute or resolving (or resolved). If IgM antibodies specific for the infection are greater than IgG antibodies - the infection is acute. If IgG antibodies predominate - the infection is later in its course or the patient has recovered and has some measure of immunity.

      
      

   3. The Biologic Effects of Antigen-Antibody Binding - The binding of specific antibody to microbial antigen leads to the elimination of the microorganism by several mechanisms:
      • Immunoglobulin coating of bacteria (opsonization) facilitates phagocytosis by WBC's and macrophages. IgG is most efficient as an opsonin. Antibody coated bacteria bind to phagocytes by way of cell surface Fc receptors which recognize the heavy chain constant region of IgG antibodies.

      • IgM and IgG bound to bacteria activate the complement system and promote the development of Membrane Attack Complexes which causes lysis of the microorganism.

      • The binding of antibody to bacterial toxins neutralizes them and prevents them from having an injurious effect on normal cells.

      • Preventing penetration of host cells by viruses. Most viruses have antigenic structures that permit them to attach to cell surfaces and invade the cytoplasm. Antibody coated viruses cannot bind to cells and therefore cannot infect them.

      • IgE antibodies can bind to Fc receptors on mast cells and trigger the release of inflammatory mediators (this is called immediate hypersensitivity).

      • Another effect of antibodies is the activation of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). When a virus invades a host cell, part of the viral outer protein envelope is deposited on the surface of the infected cell's plasma membrane. These membrane- bound proteins then become an antigenic stimulus for the production of specific antibodies by B Lymphocytes. When these antibodies bind to these cell-bound viral antigens, the infected antibody-coated cell then becomes a target for Natural Killer Cells or macrophages which destroy it.

Cell-Mediated Immunity

1. Antigen Recognition by T Lymphocytes - Antigen recognition and binding by T Lymphocytes (both CTL's and Helper T Lymphocytes) requires a special cell membrane structure called a T Cell Receptor (TCR). The T Cell Receptor is structurally different from the membrane-bound immunoglobulin molecules that serve as receptors on B Lymphocytes. TCR's are composed of two polypeptide chains (designated Alpha and Beta - responsible for antigen binding) plus a complex polypeptide called CD3 (responsible for generating intracellular signals that activate the lymphocyte). Like the immunoglobulin receptors on B lymphocytes, the antigen recognition portion of TCR's have variable regions which provide them with antigen recognition specificity. The development of TCR specificity occurs during the maturation of the T Lymphocyte in the thymus. Diversity of TCR's is derived from gene rearrangement - similar to the process of immunoglobulin gene rearrangement in B Lymphocytes. Unlike B Lymphocytes, which recognize extracellular free antigen, T Lymphocytes can only recognize antigen when it is bound to MHC molecules on the surface of infected host cells.
   1. CD4-positive Helper T Lymphocytes only recognize antigen associated with Class II MHC. As noted previously, macrophages and dendritic cells, which express Class II MHC, serve as antigen presenting cells for Helper T Lymphocytes.

   2. CD8-positive Cytotoxic T Lymphocytes only recognize antigen associated with Class I MHC. When a host cell is infected by a virus, some viral proteins are re-expressed on the infected cell's membrane in combination with its Class I MHC. Since CD8-positive Cytotoxic T Lymphocytes only recognize antigen in combination with Class I MHC, this insures that the cytotoxic response will only be directed at the infectious agent when it is most vulnerable - inside the host cell.

2. Activation of T Lymphocytes - This involves the transformation of resting T Lymphocytes into CTL's and Helper T Lymphocytes capable of eliminating antigen.
   1. The activation of resting CD8+ positive T Lymphocytes (sometimes called pre-CTL's) requires two signals: the binding of T Cell Receptor to ANTIGEN + CLASS I MHC on infected cells plus stimulation by cytokines secreted by activated Helper T Lymphocytes.

   2. Helper T Lymphocytes are activated when they recognize ANTIGEN + CLASS II MHC on an Antigen Presenting Cell. Activation of Helper T Lymphocytes is aided by cytokines such as Interleukin-2 which is produced by the Helper T Lymphocyte itself. Thus, activated Helper T Lymphocytes are "auto-stimulatory". Cytokines, such as Interleukin-1 produced by macrophages, also play a role in T Helper activation.

   3. When activated, both CTL's and Helper T Lymphocytes proliferate and undergo further differentiation (including the production of Memory T Lymphocytes).

3. Antigen Elimination Phase - The effector cells of cell-mediated immunity are fully differentiated Cytotoxic T Lymphocytes and Helper T Lymphocytes.
   1. Cytotoxic T Lymphocytes - CTL's eliminate infected cells by secreting proteins that bind to receptors on the surface of the target cell, or enters its cytoplasm, activating biochemical pathways leading to apoptosis (programmed cell death). Key features of this process include:
      • CTL killing is antigen specific. Only target cells that express the same antigen that triggered the activation of the pre-CTL are affected. Again, the antigen must be expressed on the target cell in association with Class I MHC.

      • CTL killing requires cell contact. CTL's only kill cells to which they attach. Bystander cells are not affected.

      • CTL's themselves are not injured during the elimination of target cells.

   2. Helper T Lymphocytes
      • It is important to recognize the central role of CD4+ Helper T Lymphocytes in both humoral and cell-mediated immunity. Cooperation between Helper T Lymphocytes and antigen recognizing B and T Lymphocytes is required for an effective acquired immune response. Without assistance from the cytokines secreted by Helper T Lymphocytes, differentiation of B Lymphocytes into plasma cells, and the differentiation of CD8-positive T Lymphocytes into CTL's cannot occur.

      • Activated Helper T Lymphocytes also augment the killing potential of mononuclear macrophages. Some microorganisms (e.g., Mycobacterium tuberculosis) have evolved an effective defense against phagocytosis that involves inactivating the killing mechanisms of macrophages that have ingested them. However, when affected macrophages encounter an activated Helper T Lymphocyte bearing the T Cell Receptor for the organism that has infected it, the Helper T Lymphocyte binds to the Antigen + Class II MHC complex on the macrophage, and releases gamma interferon into the macrophage reactivating its killing ability.

      • Activated Helper T Lymphocytes also secrete cytokines which function as chemotactic agents to attract neutrophils and macrophages to the site of antigen invasion. These inflammatory cells are then activated to remove the antigen by phagocytosis. This process, which takes about 24-72 hours to reach maximal effectiveness, is called delayed type hypersensitivity. A well known example of Delayed Type Hypersensitivity is the skin reaction to injection of PPD in individuals previously exposed to mycobacterium tuberculosis.

The Immune Response - Tying it All Together

The complex interactions between antigen and the immune system that results in a coordinated humoral and cell-mediated response can be illustrated by considering what happens when a virus invades the body.

1. Some of the invading viruses are taken up by phagocytic antigen presenting cells (macrophages or dendrititic cells). These antigen presenting cells enzymatically digest and express processed viral antigen on their cell surfaces in association with their Class II MHC's.

2. CD4+ Helper T Lymphocytes bearing receptors specific for the viral antigen come into physical contact with the antigen-MHC complex on the macrophage. This antigen binding, along with interleukin 1 secreted by the macrophage, activating the Helper T Lymphocyte. The activated Helper T Lymphocyte begins to synthesize and secrete cytokines - especially interleukin 2 which is auto-stimulatory to the Helper T Lymphocyte and promotes its proliferation and the production of memory Helper T Lymphocytes.

3. While Helper T Lymphocytes are being activated, B lymphocytes bearing surface immunoglobulin specific for viral antigen come into contact with free antigen or antigen expressed by antigen presenting cells. The binding of the viral antigen to specific B Lymphocyte receptors, along with exposure to cytokines secreted by activated Helper T Lymphocytes, stimulate the B Lymphocyte to proliferate and differentiate into antibody secreting plasma cells and memory B Lymphocytes. Specific antibody against the virus forms antigen-antibody complexes with the virus. This interferes with viral entry into host cells, and aids the elimination of free antigen by inflammatory cells.

4. Resting CD8+ Cytotoxic T Lymphocytes bearing receptors for the viral antigen come into contact with infected cells expressing antigen plus Class I MHC. Antigen recognition by the T Lymphocytes, along with exposure to cytokines secreted by activated Helper T Lymphocytes, stimulate the differentiation of these cells into mature CTL's. The CTL's proliferate, seek out other infected cells bearing viral antigen in association with Class I MHC, and destroy them by secreting cytotoxins. Memory CD8+ cells are also produced in this process.