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57 Cards in this Set

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Q: Describe the development and maturation of T cells.
-T cells are thymically matured lymphocytes that first undergo cell division and maturation within the thymus and then are released into the blood to circulate throughout the body. Pre-T cells arise from bone marrow stem cells and migrate to the thymus. During thymic differentiation pre-T cells acquire T cell receptors for antigen. There are two major subpopulations of T cells: Thelper and Tcytotoxic/suppressor cells.
Q: Describe the development and maturation of B cells.
-B cells have the potential to produce antibodies. Pre-B cells also arise from bone marrow stem cells. Resting B cells do not secrete immunoglobulins. The resting B cells have membrane forms of immunoglobulins as their antigen receptors. After encountering antigen, B cells divide and can later differentiate into antibody-secreting plasma cells.
Q: Why are B cells called “B” cells?
B cells have been termed "bursal equivalent" lymphocytes. Birds have an organ called the Bursa of Fabricius which is necessary for development of avian antibody-forming cells. Despite much effort, no bursal equivalent has been found in mammals
Q: What are the different types of lineages for APCs?
-can be of different lineages and include dendritic cells and macrophages, APCs are phagocytic cells that internalize or ingest, process and present antigens to T cells.
-Dendritic cells are bone marrow derived cells with characteristic markers.
-Circulating peripheral blood monocytes differentiate into adherent macrophages which can also serve as antigen presenting cells (APC).
Q: Describe MHC class I proteins.
-found in the cell surface membranes of almost all cells of the body except red blood cells. The MHC class I proteins exist as heterodimers, with an MHC I alpha chain dimerized with a small protein called beta-2 microglobulin. The MHC proteins are encoded by the major histocompatibility complex (MHC) which is a single large contiguous region of DNA. Beta-2-microglobulin is not encoded within the MHC gene complex. MHC class I proteins are recognized by CD8+ T lymphocytes. Most CD8+ cells are Tcytotoxic/suppressor cells.
Q: Describe MHC class II proteins.
-proteins found on the outer membranes of only a few of cell types, including dendritic cells, macrophages and B lymphocytes. MHC class II proteins are recognized by CD4 positive (+) T lymphocytes. Most CD4+ lymphocytes are T helper cells.
Q: Describe interleukins.
-Interleukins ("between white cells") include many different proteins that are secreted by lymphocytes, monocytes and stromal cells to serve as growth and differentiation factors for leukocytes. Leukocytes (leuko = Greek for white) are white blood cells and include lymphocytes, monocytes and granulocytes. In addition to signaling between leukocytes, many interleukins also affect additional cell types.
Q: Describe cytokines.
-Cytokines include the interleukins and are an alternative name for these small protein mediators. Cytokines usually act only within short distances from where they are produced. We now know that many cells, including non-lymphoid cells, make cytokines and that cells other than leukocytes respond. For example, beta-interferon is a cytokine made by fibroblasts, which will activate natural killer lymphocytes to kill better. (Fibroblasts are nonlymphoid cells)
Q: Describe memory T and B lymphocytes.
-T and B lymphocytes that have been clonally expanded in response to antigen (thereby increasing their total number and frequency) and have returned to the resting state. They are very long-lived cells, lasting for years. They represent selective expansion of antigen-specific cells and reenter proliferation faster than naive lymphocytes when exposed to antigens.
Q: What are the different types of cell types that Ab responses require?
-APCs (dendritic cells or macrophages), T lymphocytes and B lymphocytes. The three cell types are mobile and circulate throughout the body. However, antigen presentation and lymphoproliferation occur in lymphoid organs, not in the blood stream.
Q: What do B cells do in the Ab response?
-Ab production
Q: What do T cells do in the Ab response?
-Costimulatory 'signal 2' for B cells and growth factors for the B cells, from T cells. The costimulatory signal 2 is needed as well as the antigen 'signal 1', before the B cells can respond. The growth factors are essential for the antigen-responsive B cells to increase to sufficient numbers and to produce antibody.
Q: What do APCs do in the Ab response?
-Presentation of antigen to the T cells and costimulatory signal 2 for the T cells, comes from the APCs.
Q: What is required for a specific immune response to happen?
-Specific immune responses happen only after a particular antigen enters the body. The following stops need to be done:
(1) The B cells secrete antibodies only after antigen encounter.
(2) There are many different B cells, with different receptors for antigen. Less than one in 10^5 of the B cells can respond to the epitopes of a particular immunogen.
(3) The initial number of antigen-specific B cells is insufficient to produce significant antibody to the antigen.
(4) There is little or no antibody in circulation that will react with the antigen before the antigen is encountered.
Q: What does Ag recognition by B cells require?
-requires binding of the antigenic epitopes to membrane IgM and IgD of virgin B cells, which are the virgin B cell's receptors for antigens. Antigens in their native (undegraded) form bind to B lymphocytes. The native antigens entered via the afferent lymphatic duct. Before encounter with antigen, the B cells were 'resting' small cells, neither dividing nor secreting antibodies.
Q: What is needed for costimulatory signals to assists antigen recognition?
-Direct cell contact is needed for costimulatory signals, also called 'signal 2' to assist the antigen recognition “signal 1”. Both signals are needed for a cell to respond to antigen. There are different costimulatory signals for T and for B cells.
Q: Describe CD40 with CD40 ligand (CD40L).
-the B cell receives a costimulatory signal 2 from a T cell. The B cells move to the edge of the germinal follicles to meet the T cells which have signal 2. The T cells have taken ~3 days and already divided in response to antigen in the paracortical T cell area. During the encounter, the CD40 proteins on the B cell membranes interact with the CD40 ligand proteins (CD40L) on T cells. The CD40-CD40L interaction must occur for the B cells to differentiate into plasma cells. The B cells reside as fully differentiated, Ig-secreting plasma cells in the medullary area.
Q: Describe CD28 with B7.1/B7.2.
-T with APC. B7.1 or B7.2 proteins of B cells provide a 'signal 2' to T cells when they bind to the CD28 protein on T cells that receives this 'signal 2'. The interaction is needed to activate naive T cells. After the B cells encounter their cognate antigens (recognized by the Ig antigen receptors), they make B7.1 and/or B7.2 proteins.
Q: What role do cytokines have on Ab response?
-Several cytokines are essential for the antibody response, including IL-l, TNF -alpha and gamma interferon.
Q: Describe cytokine signaling between the APC dendritic cells (or macrophages) and T helper cells.
-this permits and then amplifies the T helper cell response. This signaling requires both IL-l and TNF cytokines, secreted by the APCs and recognized by receptors on the T cells. This signaling goes on between the antigen specific T cells in the paracortex and the interdigitating dendritic macrophages. IL-l increases the levels of g-IFN production of the T helper cells and starts an amplification loop. The g-IFN increases MHCII expression on the APes (and better antigen presentation). Better antigen presentation in MHC II-means more response to antigen and gamma IFN from the T cells. Gamma interferon was first recognized for its effects in limiting viral (virion) replication in tissue culture (hence the term "interferon").
Q: What are the major steps in generating an Ab response?
(1) Antigens (signal 1) are recognized
(2) Co-stimulation between cells provides essential interactions needed for responses to the antigens
(3) The B and T cells are clonally selected by antigen from within a large repertoire of cells that recognize different antigens, INC in numbers to form clones form each original responding cell and differentiate
(4) cytokines are made
(5) at the end of the response, there is memory
Q: Describe the process involved in antigen recognition.
-antigens are recognized by both B and T cells
-B cells recognize native (intact, unprocessed) antigen. Their antigen receptors are immunoglobulins.
-T helper cells recognize antigens derived from foreign proteins that are proteolytically processed into peptides of 30 amino acids or fewer. The processing is done by the APCs, including the interdigating dendritic cells. The peptides are presented to T helper cells in MHC class II proteins. T helper cells recognize the combination of peptide and MHC class II protein. Free peptides alone (without MHC) are unrecognized by T helper cells.
Q: Describe the co-stimulation between cells.
-B cells get their second signal through their CD40 molecules. The CD40 molecules interact with CD40L (CD40 ligand) molecules on T cells.
-T cells get their second signal through their CD28 molecules. The CD28 molecules interact with B7.1 or B7.2 molecules on the APCs. The B7.1 and B7.2 molecules may also be expressed by B cells.
Q: Describe clonal selection of B and T cells.
-The B cells divide clonally in the germinal follicles. Some become plasma cells, move to the medulla of the lymph nodes, and secrete antibodies. It takes about 5 days to begin production of plasma cells.
-The T cells divide clonally in the paracortex. Some become T helper cells, others Thelper2 cells. Some become memory T helper cells.
Q: Describe cytokine production.
-done to support the Ab response
-The dendritic cells and macrophages make IL-l and TNFalpha.
-Both T cells and B cells need TNFalpha to respond to antigen.
-The Thelper cells make gamma interferon (gIFN) and IL-2. The Thelper type-2 cells make IL-4.
-B cells need gIFN, IL-2 and IL-4 to divide and differentiate and produce antibodies.
Q: Describe what happens at the end of the Ab response.
-At the end of the response, there is "memory". Antigen is cleared. Memory B and memory T cells and antibodies circulating in blood remain for the lifetime of the individual.
Q: Describe antigen recognition by the T helper cells.
-The immunogen for T cells in Figure 1 is usually carried into the lymph nodes from the periphery by Langerhans dendritic cells. The immunogen must be processed by the dendritic cells or there will be no immune response. These dendritic cells internalize, ingest, digest, and present protein pieces (peptides) to the T cells.
Q: How do dendritic cells and macrophages process antigens?
-by ingestion of immunogenic proteins and by proteolytic digestion of the immunogens to small peptides. The antigenic proteins were originally synthesized extracellularly or exogenously of the APCs. The APCs may have ingested the antigens at the site of infection and then traveled to the lymph node. They will have proteolytically digested the antigen by the time they arrive in the paracortical T cell area of the lymph node. The antigenic pep tides are bound to and physically associated with class II majot histocompatibility (MHC) molecules. The antigenic peptide-MHC class II association occurs when MHC class II proteins encounter peptides from digested proteins. The MHC class II protein-antigenic peptide complex is subsequently transported as one unit to the APC cell surface. B cells as well as dendritic cells and macrophages can present antigens to T helper cells, provided that the antigenic peptides are bound to MHC class II proteins. These B cells also endocytose and proteolytically process externally acquired protein antigens.
Q: Do dendritic cells and macrophages divide in the lymph nodes?
-Dendritic cells and macrophages do not divide in the lymph nodes and are not specific for particular antigens. In fact, one APC can process and present.
Q: Describe how carrier proteins are digested into peptides by APCs and later sent to the APC surface in association with MHC class II molecules.
(1) uptake of extracellular proteins into vesicular compartments of APC
(2) processing of internalized proteins in endosomal/lysosomal vesicles
(3) biosynthesis and transport of class II MHC molecules to endosomes
(4) association of processed peptides with class II MHC molecules in vesicles
(5) expression of peptide-MHC complexes on cell surface
Q: What do T helper cells recognize?
-T helper cells recognize only processed antigens. T' Cell Receptors for antigen (TCRs) recognize protein antigens only as peptides bound by other proteins. The TCR of T helper cells recognizes foreign protein antigens only when bound by class II MHC proteins not as free peptides. Regions of both the MHC class II molecule and the processed peptide bind to the helper T cell's TCRreceptor. The T helper cells use CD4 as the co-receptor for antigen, binding to parts of MHC II molecules
Q: What are some B cell growth and differentiation factors?
-gIFN and IL-2 are made by Thelper-type 1 cells
-IL-4 is made by Thelpertype2 cells. High levels of IL-4 drive differentiation to IgE plasma cells.
-IL-5 is made by various T helper cells. High levels of IL-5 drive differentiation to IgA plasma cells.
Q: What are some T cell growth and differentiation factors?
-IL-2, made by the T helper cells is an essential growth factor for the T cells as well as the B cells.
Q: What are some crucial molecular changes that occur within each cell type to promote the response to antigen?
-T helper cells have to convert their receptors for IL-2 into high affinity receptors
-CD25, a chain of the high affinity IL-2 receptor, is induced during T cell activation
-after activation, T helper cells begin to express mRNAs for many interleukins and then start to secrete these ILs
Q: Describe CD25.
-a single chain protein that comprises part of a trimeric high affinity cellular receptor for IL-2
Q: In order for T helper cells to specifically react with antigen, what must they acquire on their membrane?
-T helper cells that specifically react with antigen have to acquire high affinity receptors for IL-2 before they can proliferate. Resting T cells have the intermediate affinity IL-2 receptor, comprised of a beta chain and a gamma chain. When T cells make a new protein termed CD25, a trimeric high affinity IL-2 receptor is expressed on the cell surface of activated T lymphocytes
Q: What else uses the gamma common chain of IL-2 receptor?
-The gamma common chain of the IL-2 receptor is also used by the receptors for IL-4, IL-7, IL-9, IL-15 and IL-21
Q: Describe T helper cell expression of mRNAs for ILs.
-T helper cells secrete interleukin 2 (IL-2), which is an essential T and B cell growth factor. The T cells simultaneously use their own new high affinity receptors for IL-2, so that IL-2 has an atocrine function for growth of the T helper cells. The increased numbers of T cells in turn secrete more IL-2 and other cytokines. IL-2 from the T cells also has a paracrine function for the growth of B cells.
-T cells also secrete interleukins 4 and 6 which are necessary for B lymphocyte I proliferation and differentiation.
-After primary responses, some of the antigen-responsive T cells become memory cells (which have the same antigen receptors).
Q: What are the key cell surface proteins of APCs?
-MHC class II proteins and gamma interferon receptor
Q: Describe the MHC class II proteins.
-The MHC class II proteins acquire peptides derived from the immunogen. The class II MHC proteins are two membrane proteins, that are noncovalently associated with each other. The alpha chain is the larger of the two proteins with a molecular weight of 34,000, the smaller beta chain has a m.wt. of 29,000. Both alpha and beta proteins must associate to hold and present the antigenic peptides. (Note: MHC class II proteins do not rearrange their DNA. Cells express class II proteins exactly as they are encoded.) Class II molecules are found on B lymphocytes as well as macrophages, and in low amounts on T lymphocytes. Occasionally, class II MHC proteins are found on damaged endothelium, but class II proteins are not on other normal tissues. Class II proteins are not on red cells, either.
Q: Describe the gamma interferon receptor.
-Gamma interferon from T helper cells binds to the macrophage gamma interferon receptors
Q: What are the key cell surface proteins of T helper cells?
-TCR receptor for antigen, CD3 protein, CD4 membrane protein, CD2, CD40L, CD28
Q: Describe the CD3 proteins.
-are accessory molecules and signal transducing proteins associated with the T cell receptor.
-"CD" is an acronym for "clusters of differentiation". CD proteins are defined by their reaction with specific mouse monoclonal antibodies to different monoclonal antibodies are found on different cell lineages.
Q: What binds with the CD3 receptors?
-Both the alpha-beta and the delta-gamma TCR T cell receptors are physically associated with CD3 T cell membrane proteins. The T cell receptors themselves lack the cytoplasmic domains for signal transduction. CD3 proteins are found only on T cells. There are different proteins in the CD3 complex: CD3gamma
Q: Describe the CD4 membrane protein.
-is the co receptor for MHC II proteins, binds to MHC II proteins and is found primarily on helper T cells. The CD4 molecules of the helper T cell physically bind to the MHC class II proteins, providing stability and enhancing recognition of the antigen held within the MHC class II proteins.
-CD4 binds CD4+ T cells to other cells bearing MHC class II proteins. Thus CD4+ T cells always recognize antigens associated with MHC class II proteins. Most (but not all) CD4+ T cells are helper T cells that secrete lymphokines
Q: Describe the CD2 cell surface protein.
-All T lymphocytes have CD2 cell surface proteins. CD is an adhesion molecule that binds to another molecule, termed LFA3 (lymphocyte functional antigen 3) which is found on other cells. CD2-LFA3 interactions hold cells together to promote cooperation.
Q: What are the important B cell surface proteins?
-MHC Class II proteins, IL-2 receptors, B cell receptors for each of the individual B cell growth and differentiation factors, B7.1 and B7.2 proteins, CD40
Q: Describe the MHC class II proteins.
-B cells normally have low levels of MHC class II proteins on their cell surface. Much higher levels of class II proteins are induced by gamma interferon, thereby allowing B cells to present antigenic peptides.
Q: Describe IL-2 receptors.
-B cells acquire the intermediate affinity IL-2 receptor p75 so that IL-2 can serve as a B lymphocyte differentiation factor.
Q: What are interleukins?
-Interleukins are small (10-30 ill) secreted proteins that affect the immune system. They may also affect other aspects of the inflammatory response, as does pyrogenic IL-l.
Q: What are the 5 monocyte/dendritic cell-derived ILs (monokines) that we chould remember?
-IL-1 and TNF-alpha, 3 colony stimulating factors (CSFs)
Q: Describe IL-1 and TNF-alpha as interleukins.
-they both affect T and B lympocytes
-IL-1, TNF-alpha and the complex of processed antigen plus MHC class II are all necessary to activate T helper cells. IL-1 is also the leukocytic pyrogen which causes fever by signaling the hypothalamus.
-TNF alpha is necessary for B lymphocyte activation from the resting state and also INC the cell surface density of IL-2 receptors on T cells
Q: What are the colony stimulating factors (CSFs)?
-Granulocyte/macrophage CSF (GM-CSF) , which promotes growth of both granulocytes and macrophages in the bone marrow.
-Granulocyte CSf (G-CSF), which promotes growth of only granulocytes in the bone marrow
-Macrophage CSF (M-CSF) that stimulates bone marrow production of macrophages.
Q: What are some important lympkines form T helper cells?
-Gamma interferon (IFNr) which increases MHC class II expression. Gamma interferon also activates natural killer (NK) lymphocytes to kill more effectively.
-IL-2 is the major T cell growth factor, but also affects B cell differentiation and activates NK cells to kill more effectively.
-IL-4 and IL-6 are B cell growth and differentiation factors. IL-4 helps pull the switch so that B cells can convert to secretion of IgE.
Q: What are some important lymphokines from T helper cells that do not need to be memorized?
-1L-3 stimulates myeloid precursors in the bone marrow
-IL-5 affects differentiation of eosinophils and the IgA switch.
-IL-10 is Cytokine Secretion Inhibitory Factor (CSIF) which comes from T helper and T suppressor cells to turn off interleukin production.
Q: What are the different subsets that CD4+ T helper cells are found in that produce different ILs?
-THO (type O) uncommitted T helper cells. IL-12 causes THO (uncommitted T helper cells) to differentiate into THI cells. Under IL-12 stimulation, TH2 cells are not made. Thus IL-12 favors T cell effector responses and reduces antibody production.
-THl (type I) cells that secrete IL-2 and gamma interferon and not IL-4.
-TH2 (type 2) cells that secrete IL-4 and not gamma interferon. TH2 cells are very good at supporting B cell growth and differentiation. T H2 cells make interleukin 10, the cytokine that effectively turns off interleukin-2 dependent T cell division.
Q: What are the medical perspectives for T-B-APC cooperation?
-The need for multicellular cooperation means that antigens have to have both epitopes for B cells and protein peptide epitopes for T helper cells. The need for two forms of antigen, recognized by two types of cells, creates a failsafe environment to reduce autoimmune responses.
-Vaccines should be injected into sites where the proteins will be subjected to immune cellular cooperation. Intradermal injection supports reactions with Langerhans cells, that carry antigens into lymph nodes. Subcutaneous injection is good for strong antigens that do not need adjuvants. Vaccines with adjuvants are given Intramuscularly because the very strong macrophage response could produce ulcerous skin lesions. Vaccines injected into veins will not support strong responses