Immunology B cells and Antibodies – humoral T cells and T cell receptors – cell mediated MHC –HLA DQα is part of the MHC How MHC, B, and T cells work together

Specific Defenses of the Host Part 1 acquired or adaptive immunity i.e., you must be “exposed”

Specific Defenses of the Host Called acquired or adaptive immunity. Although one is born with a general ability to respond to foreign invasion of the body, the specific response is developed during a person’s lifetime. Immunity, unlike resistance, involves the production of a specific defensive response against the particular type of foreign organism or substance that has invaded the body.

The immune system contains two components cell-mediated arm (more later) humoral arm of the immune system involves antibodies (also called immunoglobulins) that are dissolved in blood and lymph Antibodies are produced by B lymphocytes upon exposure to a foreign antigen Lymphocyte – a type of cell found in the blood Antigen – anything that can stimulate a specific immune response

The Structure of a Monomeric Antibody

Immune system, continued B cells have antibodies on their cell surfaces and the antibodies act as surface receptors for the antigen. Sometimes called B cell receptors The antibody actually recognizes only a small region of the antigen called the antigenic determinant. Most antigens have many possible different antigenic determinants.

Antigenic determinants

Immune system, continued Each B cell has many identical antibodies on its surface. The specificity of each antibody on the surface of a single B cell is the same. In other words, all of the antibodies on the surface of a single B cell recognize the same antigenic determinant. After binding of the antigen (specifically, the antigenic determinant) to the antibody on the B cell surface, the B cell is stimulated to proliferate and to differentiate into a plasma B cell that will produce and secrete antibody of the same specificity that was on the surface of the B cell. These secreted antibodies are dissolved in the plasma of the blood.

Antigens and B cell receptors

Secretion of antibody following B lymphocyte stimulation This picture represents an overview of multiple steps.

Immune System, continued Therefore, the plasma cell produces antibody that will specifically react with the antigen (specifically, the antigenic determinant) that stimulated its production. Both circulating antibodies and membrane-bound B cell receptors can recognize and bind to: linear proteins folded proteins (may recognize non-linear sequences) polysaccharides nucleic acids

Linear Versus Non-linear Antigenic Determinants

Immune System, continued The second arm of the immune system is called the cell mediated arm of the immune system. Involves T lymphocytes that are found in blood and lymphoid tissues. T cells, like B cells, have receptors on their cell surface (called the T cell receptor) that recognize and bind to antigens (or, more specifically, antigenic determinants). The T cell receptor is similar in structure to an antibody, but is never found secreted into the blood. Therefore, cell-mediated

Structure of the T cell receptor

Immune System, continued All of the T cell receptors on the surface of a single T cell recognize the same antigenic determinant. The T cell receptor is capable of recognizing only antigenic determinants that are linear pieces of proteins (peptides). The significance of this will become clear later in the lecture. After the T cell receptor is bound by its specific antigenic determinant, the T cell will be stimulated to proliferate and differentiate into an effector cell. There are several different types of effector cells (helper, supressor, cytotoxic or cytolytic, etc.) T cells do not produce antibodies.

Effector T cells Antigen presenting cell is part of the immune system. Target cell is any cell in the body that has become infected. T cells recognize antigens only when bound to MHC molecules.

Mechanisms of the Immune Response Both B and T cells have an antigen independent and an antigen dependent phase of maturation. Antigen independent maturation Pluripotent stems cells in the bone marrow produce immature B cells that mature to immunocompetent B cells in the bone marrow. Immunocompetent B cells have surface membrane-bound antibodies and are capable of functioning in an immune reaction.

Mechanisms of the Immune Response, continued Pluripotent stem cells in the bone marrow produce immature T cells that move to the thymus where they mature into immunocompetent T cells which have T cell receptors on their surface that are capable of interacting with an antigenic determinant in an immune response. In the thymus those T cells that respond to self-antigens are eliminated. Thus, the immune system does not normally produce a specific immune response against self-antigens.

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Antigen independent maturation

Mechanisms of the Immune Response, continued Antigen dependent maturation begins when antigen (antigenic determinant) binds to a B cell receptor (membrane-bound antibody) on the surface of a B cell or a T cell receptor on the surface of a T cell. Binding of the antigen will stimulate a clonal expansion (proliferation) and differentiation of the B or T cell. Antigen binds only to those B or T cells that are making a receptor with a good “fit”.

Mechanisms of the Immune Response, continued Antigen dependent maturation of B cells B cells will differentiate either into plasma cells that will secrete antibody of the same specificity (recognizes the same antigenic determinant) that was on the surface of the original B cell or into memory B cells.

Antigen dependent maturation of B cells

B cell clonal expansion

Mechanisms of the Immune Response, continued Antigen dependent maturation of T cells T cells will differentiate either into an effector cell (helper, supressor, cytotoxic or cytolytic, etc) or into a memory cell.

Antigen dependent maturation of T cells

Mechanisms of the Immune Response, continued Memory B or T cells Memory cells are responsible for the anamnestic or secondary response that occurs the next or subsequent times that the same antigen is encountered. (The immunity has been acquired.) The anamnestic response is usually much quicker or stronger than the primary or original response.

Mechanisms of the Immune Response, continued B cells and macrophages often work together with T cells during an immune response. When an antigen comes in, B cells and macrophages will process the antigen and present pieces of it (antigenic determinants) to a T cell for stimulation. T cell can stimulate another B cell presenting the same antigen (one of the possibilities during the effector phase). Look two slides back. What cell surface molecules are involved?

Mechanisms of the Immune Response, continued (keep track of T, B, and APC cells)

Mechanisms of the Immune Response, continued For many antigens, T cell interaction is required for B cell stimulation and production of secreted antibodies. For “T dependent” antigens, T help (from T helper cells) is required for B cell stimulation. T dependent antigens are all protein antigens that contain some epitopes recognized by T cells and other epitopes recognized by B cells. Stimulation of the B cell in a T-dependent response requires two signals. One signal comes from the binding of the antigen itself to the B cell receptor (membrane-bound antibody). The second signal comes from an interaction of the B cell with a T cell.

Mechanisms of the Immune Response: T-Dependent Antigens Stimulation of the B cell requires 2 signals. (More detail on the two signals 2 slides back.) More steps later. < 1/100,000 of any individual’s immunocompetent lymphocytes are specific for any one antigen

IgM, IgG Isotype switching – Affinity maturation Mechanisms of the Immune Response, T Dependent Antigens Some definitions for previous slide IgM, IgG 2 of 5 different isotypes, M,G,A,D,E Isotypes differ with respect to the form of the heavy chain. Isotype switching – Also known as “heavy chain class switching” A step in B cell maturation Each of the different heavy chain types is optimal for eliminating certain types of microbes. Affinity maturation A step in B cell maturation that occurs in the germinal centers of the lymph nodes. Isotype switching also occurs in cells that undergo affinity maturation. Memory cells may be derived either before or after affinity maturation.

Mechanisms of the Immune Response, continued T helper cells have CD4 on their cell surfaces. The significance of this will be explained later. You will later hear that cytotoxic T lymphocytes have CD8 on their surfaces. The T helper cell must be armed by previous exposure to the same antigen as the B cell which it helps. However, it also “helps” the first such B cell that it encounters. The T cell is also restricted in that it can help B cells produced only by the same individual that produced the T cells. This is because the T cell can recognize the foreign antigen only in the context of a self-antigen (an MHC complex).

Mechanisms of the Immune Response, T Dependent Antigens Note that the B cell surface antibody recognizes one epitope of the antigen while the helper T cell recognizes another epitope in the context of an MHC Class II molecule. The antigen is the same (even though it doesn’t look like it), but the epitopes (or antigenic determinants) differ. In the B cell, some crosslinking of membrane bound antibodies must occur.

B-T interaction

B-T interaction Note the role of CD4! Based on what you know about B cell maturation, what response from the B cell to the cytokine stimulation would you expect?

Mechanisms of the Immune Response, continued T help is not required for B cell stimulation in response to “T independent” antigens. T independent antigens are usually in the form of a repeating subunit like a polysaccharide, lipid, or nucleic acid, not a protein. Binding by this type of antigen somehow provides both signals that are required for B cell stimulation (by causing extensive cross-linking of the surface antibodies?) The outcome from this type of stimulation is clearly different from that which occurs in T-dependent stimulation, since with the T-independent stimulation no memory cells are made. There is no anamnestic response for T-independent antigens.

T-independent activation of B cells How does the response differ from T-dependent activation? Compare with slide #29.

Mechanisms of the Immune Response, continued Cytotoxic T lymphocytes (CTLs) have CD8 on their surfaces (significance will be described later) and they act to destroy target cells, including infected cells, cancer cells, and tissue transplants. Cytotoxic T cells are like T helper cells in that, in order to function, they can only recognize a foreign antigen in the context of a self-antigen (MHC complex). The T cell restriction (for both T helper cells and cytotoxic T cells) involves proteins (sometimes called antigens) encoded in the Major Histocompatibility Complex (MHC).