Innate and adaptive immunity The immune system has various mechanisms to eliminate pathogens that get past physical barriers. These include both innate and adaptive immune responses. These work together to result in the destruction of invading pathogens. Innate immunity (natural immunity): –not specific for a given microbe –act quickly, without the need for amplification of microbe- specific cells that is seen in adaptive responses, providing the first line of defense to microbial infection

Adaptive immunity (acquired immunity): –highly specific for a given infectious agent, –more vigorous on subsequent exposure to the same agent –characterized by memory, amplification of responses, and specificity

Recognition of Antigen by T and B cell Receptors T cell receptor (TCR) and the B cell receptor (BCR, or surface immunoglobulin) for antigen appear to have a similar structure Also, both exhibit significant diversity, with somatic recombination (DNA rearrangements) being responsible for most of this diversity However, there are several fundamental differences between these molecules:

One important difference: –the B cell antigen receptor (surface immunoglobulin), when secreted and present in serum or other fluids as an antibody, can exert its effector function, –the T cell antigen receptor is found only as a cell surface- associated molecule Antibodies can: –neutralize bacterial toxins by binding directly to these molecule –enhance phagocytosis by inducing opsonization –activate the complement cascade, resulting both in lysis of pathogens, as well as in their enhanced opsonization and chemotaxis

The T cell antigen receptor operates only as a cell surface- associated antigen-recognition molecule, and is not secreted In fact, T cell-mediated effector functions are not actually carried out by the TCR itself, in contrast to antibody molecules, which can carry out several types of effector functions in dealing with pathogens T cells exert their effector functions primarily by secreting cytokines, or by acting as cytotoxic cells While these functions do involve the TCR as a means of restricting specificity, the TCR itself does not exert these activities

Antibodies (Ab) are soluble antigen-reactive molecules, which are found in high concentration in serum, and are produced by B cells. An antibody molecule has two antigen-binding sites per molecule (variable regions), and a constant region, which plays important roles in antibody effector function.

Antibodies are composed of two identical heavy chains and two identical light chains Each light and heavy chain has a variable and constant domain(s) - these combine to give a molecule with a constant and variable regions (form the antigen-binding site).

A cell surface-associated form of the immunoglobulin molecule acts as the cell-surface receptor for antigen on B cells Cross-linking of surface Ig by antigen initiates the activation of B cells When B cells are stimulated to make and secrete antibodies, these secreted antibody molecules correspond to the surface immunoglobulin expressed by those cells

There are various immunoglobulin classes, or isotypes - subtypes of antibody molecules The constant region of each of these immunoglobulin subclasses differs, resulting in different biological functions

The TCR forms part of the T cell receptor complex on T cells. This TCR complex is involved not only in recognizing antigen, but also participates in the stimulation of signaling that results in T cell activation.

Another significant difference between antibodies/immunoglobulins and the T cell receptor is that antibodies (and B cells) can recognize intact antigens from pathogens, while T cells do not The T cell receptor can only recognize antigens when fragments of these antigens are displayed by specialized antigen-presenting molecules on the surface of antigen-presenting cells (APC) - MHC (major histocompatibility) molecules This difference is what allows antibody molecules to interact with antigen when in solution, while T cells have to “see” antigen in the context of an antigen-presenting cell

Antigen-presenting cells (APC) take-up and process antigen, allowing antigen- derived peptides to associate with MHC molecules There are two types of MHC molecules that are important in presenting antigen to T cells: –MHC class I –MHC class II

MHC class I molecules present antigens from intracellular pathogens, such as antigens encoded by viruses Since MHC class I molecules operate as a sort of surveillance system for intracellular pathogens, especially viruses, these molecules are expressed on all nucleated cells

MHC class II is involved in presenting antigens that antigen- presenting cells take up from their extracellular environment, such as antigens that are produced by bacteria. Expression of MHC class II is restricted to specialized antigen-presenting cells, so MHC class II is not expressed as widely as MHC class I.

Immune responses are sometimes categorized as humoral responses or cellular responses. The term humoral immunity refers to forms of immune function that can be transferred with the transfer of serum – primarily antibody-mediated immunity, since antibodies are soluble molecules present in serum. Serum therapy, the passive transfer of humoral immunity by giving patients serum from an immune animal or person, was common some years ago, and is still utilized in some situations.

Immune responses that could be transferred by the transfer of cells, but not of serum, from one animal to another were referred to as cellular immunity, or cell-mediated immunity. Cellular immunity is primarily due to the actions of T cells, which do not secrete their antigen receptor, and which need to be present to exert the types of immune responses that they are responsible for.

T Cell Subsets There are two major subsets of T cells, CD4-positive cells and CD8-positive cells. CD4-positive T cells are helper/inducer cells CD8-positive T cells are cytotoxic T cells CD8 CD4

These different T cell subsets interact with different MHC molecules: –helper/inducer T cells (CD4) : MHC class II –cytotoxic T cells (CD8) : MHC class I CD4-positive T cells, which interact with MHC class II-positive antigen-presenting cells, are specialized for the induction of responses to extracellular antigens

These are two types of CD4 helper T cells: –TH1 cells –TH2 cells These CD4 subsets are defined by the pattern of cytokines that they produce, and they have markedly different biological effects, and help induce different sorts of immune responses.

CD8-positive T cells, which interact with MHC class I-positive antigen-presenting cells, are specialized for the induction of responses to intracellular antigens CD8 cells, when stimulated, become cytotoxic killer cells.

There are different types cells that can function as of antigen- presenting cells. Specialized or professional APC include: –dendritic cells –macrophages –B lymphocytes All of these cells express significant levels of MHC class II molecules on their surface, and can take up and process and present antigen to CD4-positive T cells. Dendritic cells also are very effective at stimulating CD8 T cell activation, inducing these cells to become cytotoxic T cells.

CD4 and CD8 molecules play a direct role in APC:T cell interactions, binding to MHC class II and class I, respectively. This ensures that MHC class I presents peptides to, and stimulates, CD8 T cells, and that MHC class II interacts only with CD4 cells.

Lymphoid Tissue The different types of cells that make up the immune system are distributed in blood and tissues, as well as in lymphoid tissues/organs. Cellular interactions are necessary to kick-off immune responses – these interactions occur in lymphoid tissues. In addition to this, the development of the cells of the immune system also takes place in other types of lymphoid tissue.

Lymphoid organs can be divided into: –primary lymphoid organs, such as the thymus and bone marrow - where lymphocytes develop and undergo maturation –secondary lymphoid organs, such as the spleen and lymph nodes - where mature lymphocytes hang out and interact with antigen and with each other, in the course of initiating and carrying out immune responses The cells of the immune system develop from pluripotent stem cells, which reside in bone marrow. Differentiation of these stem cells is induced by interactions with the bone marrow stromal cells, especially by certain cytokines produced by these cells.

B and T cells undergo distinct differentiation pathways. B cells are generated in the bone marrow, with mature B cells, which are ready to respond to antigen, migrating to lymph nodes and spleen.

Tolerance is the induction of non-responsiveness to a particular antigen, resulting in the inability to respond to that antigen. Tolerance to self-antigens is a central feature of the immune system. Loss of tolerance to self antigens can result in the destruction of self-tissues by the immune system, resulting in autoimmune disease. Tolerance to self-antigens is induced in both B and T cells during their development. The induction of tolerance to selected non-self antigens (transplanted tissue) would be a great thing to be able to achieve:

T cell precursors leave the bone marrow, go to the thymus, where they mature, with mature T cells then migrating to secondary lymphoid organs. The thymus is a primary lymphoid organ that is specialized for the generation of mature, antigen-responsive T cells. bone marrow thymus 2 o lymphoid organs

The cellular interactions between APC and helper T cells, and between activated helper T cells and other lymphocytes, involve both direct cell- cell contact, mediated by cell-surface stimulatory and adhesion molecules, as well as the production of cytokines. These interactions occur primarily in the peripheral lymphoid organs (lymph nodes and spleen), also called secondary lymphoid organs. These are specialized for the trapping of antigen, and for allowing interaction of APC and T cells, and leading to the initiation of immune responses.

Lymph nodes are kidney shaped organs that filter lymph. Lymph nodes contain B cell-enriched areas (follicles in the cortex) and dendritic cell and T cell-enriched areas (the paracortical area). Germinal centers are areas of proliferating B cells interacting with T cells and antigen.

Lymph draining the extracellular spaces carries antigens from the tissues to the lymph nodes, entering via the afferent lymphatic vessel. This brings soluble antigen in contact with various types of APC, including dendritic cells, macrophages, and B cells.

The spleen is a fist-sized organ that filters antigens from blood, and is composed of two types of tissue, white pulp and red pulp. The red pulp contains erythrocytes. The white pulp contains arterioles surrounded by lymphoid cells, including T cell and a B cell-enriched areas.

Introduction to immunology concepts innate and adaptive immunity –rapid vs. slow –not antigen-specific vs. highly-specific –not amplified on 2 0 exposure vs. strongly amplified + memory cells involved in immune responses –lymphocytes (B and T cells, T cell subsets) –phagocytic cells, antigen-presenting cells specific recognition of antigen –T cell receptor (TCR), B cell receptor and antibodies –antibodies can “see“ antigens in their native form, the TCR “sees” Ag only when processed and presented appropriately –MHC – interactions with antigen and TCR –clonal selection lymphoid tissue –1 0 lymphoid tissue – where lymphocytes develop –2 0 lymphoid tissue –lymphocytes & APC interact to initiate immune responses