Immuno T cell Subsets (7/8)

• the catabolism of protein into peptides inside a host cell
• some peptides will go on to bind to MHC molecule

• a peptide & MHC are presented on the surface of a host cell
• will go on to be recognized by a TCR on either a CD4+ or CD8+ T cell

• pathogens are taken up by specialized host cells, APCs, and are not pathogenic but still foreign
• “harmless” antigens

derived from inside a host cell as a result/product of the cell being infected by a foreign pathogen

• occurs using MHC class II pathway (eg. dendritic cells, macrophages)
• 1. antigen is taken into acid vesicles & broken down into peptides
• 2. vesicles containing broken down peptides merge with vesicles containing newly synthesized MHC class II molecules
• 3. peptide-MHC class II is presented on the surface of the cell to CD4+ T cells

• occurs using MHC class I pathway
• 1. antigen catabolized (degraded) in cytoplasm by proteasome
• 2. peptides transported to ER
• 3. peptides associate & selectively bind to newly made MHC class I molecules (still happening in the ER)
• 4. peptide-MHC class I complex moves from the ER to the golgi & is presented on the surface of the cell for interaction w/ CD8+ T cells

• peptides must be 8-9 amino acids long
• this length fits into the peptide-binding groove of the MHC class I molecule
• there are fewer peptide size restraints in respect to MHC class II molecules (can have 12-20 AA long peptides binding)

• it can up-regulate both MHC class I & II processing
• in contrast, viruses/tumors can down-regulate processing, especially endogenous in MHC class I presenting cells

it does NOT trigger an immune response

mechanism by which dendritic cells can showcase peptides derived from exogenous antigen processing & present them to CD8+ T cells

• upside: the combination of HLA & peptides invoke a protective response in response to certain diseases (eg. malaria)
• downside: the large diversity sometimes confers pathology in those particular individuals who have HLAs that are anti to self peptides
• there's an evolutionary advantage

• MHC class II presenting a peptide expressed on the APC surface
• TWO SIGNALS TOTAL are required for CD4+ T cell activation
• signal #1: MHC class II + peptide --- TCR
• signal #2: between costimulators

• molecules required in addition to the TCR to activate naïve (have not yet encountered antigen) T cells via signal transduction
• costimulators on T cell surface interact with molecules on the surface of an APC to provide a costimulator (2nd signal)
• eg. CD28 (T cell) --- B7 (APC)
• CD40 Ligand/CD40L/CD154 (T cells) --- CD40 (APC)

• APC: induced AFTER exposure to pathogen
• T cell: some up-regulated during response

the dendritic cell

• pathogens induce maturation of dendritic cell in tissues
• phagocytosis and antigen processing of pathogens up-regulates MHC class II & costimulators, changing the surface of the dendritic cell
• causes DC to migrate out of tissue --> the draining lymph node

• a molecule (frequently synthetic) that upregulates costimulators & TLRs on APCs to give primary response a boost
• necessary because many harmless molecules do not produce an immune response

• 1. CD4 moves closer to TCR & pulls with it kinases
• 2. activated Zap-70 sends a message & activates 3 different sets of pathways
• 3. transcription factors are activated --> move into nucleus and transcribe genes (occurs within ~72 hours after initial activation)

• 1. cytokine genes (*IL-2)
• 2. cytokine RECEPTOR genes (IL-2Rα chain)
• 3. homing molecule gene expression is changed (cell surface molecules that influence where cells moves in body)

activated T cells leave the lymph node and move into tissues, generally at the site where pathogen was first encountered

• T cell growth factor
• the binding of IL-2 to its high-affinity receptor (IL-2R) expressed on activated T cells results in huge proliferation & clonal expansion of antigen-specific T cells

• it stabilizes IL-2 mRNA
• in the absence of this signal, IL-2 mRNA is rapidly degraded
• (B7 on the APC/DC, CD28 on the T cell)

• it complexes with calcineurin, INHIBITING T cell activation & preventing cytokine synthesis that activates effector cells to reject the foreign tissue
• calcineurin: phosphatase that ACTIVATES T cells

• cell that is now ready to exert its function
• the change in honing & adhesion molecules on the surface of the cells as a result of gene rearrangement transforms a naive T cell --> effector T cell

• which synthesize and secrete a vast array of cytokines
• act as helper cells for B cell antibody synthesis, & CD8+ T cells, which directly kill cells

• one cytokine can act on many different cells
• many different cell types can make the same cytokine

• 1. autocrine = affects the same cell
• 2. paracrine = affects nearby cells
• 3. endocrine = secreted into the circulation

• T_H2 cytokine that induces B cells to syntheze IgE
• synthesized by CD4+ T cells (T_H2), mast cells, & others
• (anti-IL-4 agents used to treat some forms of asthma)

• T_H2 cytokine that activates eosinophils
• anti-IL-5 agents used to treat some forms of asthma

• signature T_H1 (a CD4+ T cell subset) cytokine that activates NK cells & macrophages to participate in cell-mediated immunity & kill infected cells of the body
• also induces B cells to switch to synthesizing antibody isotypes that activate complement (key effector pathway in the response to many types of bacteria)

• activates cells in the inflammatory response
• synthesized by macrophages and NK cells
• (anti-TNFα agents are used to combat rheumatoid arthritis)

• T_H1: IFNγ, IL-2
• T_H2: IL-4, 5, 13
• T_H17: IL-17, 22
• Treg: TGF-β, IL-10

• cytokines: IFNγ, IL-2
• act on macrophages, NK cells, CD8+ T cells, B cells to make IgG3
• cell mediated immunity
• killing of virus/bacterially infected host cells

• cytokines: IL-4, 5, 13
• act on eosinophils, B cells to make IgE & IgG₄
• respond to WORMS & allergens

• cytokines: IL-17, 22
• act on neutrophils, epithelial cells (especially at mucosa)
• are pro-inflammatory & respond to fungi/extracellular bacteria

• cytokines: TGF-β, IL-10
• act on other lymphocytes to INHIBIT the function of other sets of T & non-T cells
• (Treg cells themselves express CD25)

• cells of the innate immune system, particularly dendritic cells
• innate immune system cells shape the adaptive immune response
• IL-12 --> T_H1 cell development
• IL-4 (source unclear) --> T_H2 cell development

• this results is a skewed pattern of the CD4+ T cell responses
• IFNγ & IL-2 made by T_H1 INHIBIT T_H2's from making IL-4, 5 & 13
• (the reverse applies as well)

• CD4+ T cells that interact with B cells to induce antibody synthesis
• occurs in secondary lymph node germinal centers
• CD4+ T cells are required for most B cells to synthesize antibody in response to a TD-antigen

• how in response to a TD antigen the cooperating Helper T & B cell may respond to different parts (epitopes) of a single antigen peptide, but the epitopes are part of the same protein
• this linked recognition occurs in the germinal center of secondary lymphoid organs (eg. lymph nodes)

• 1. BCR (B cell receptor = antibody) binds to antigen
• 2. antibody/antigen complex is taken up by cell
• 3. antigen is broken down in acid compartments to smaller peptides
• 4. specific antigen peptides bind to MHC class II
• 5. peptide-MHC class II complexes are trafficked to the cell surface
• 6. here it interacts with a CD4+ T cell that has the matching TCR for the antigen peptide (1st signal…)
• 7. CD4+ T cell CD40L binds to B cell CD40 (2nd signal) -->
• B cell makes antibody & T cell is activated to proliferate cytokines

• T_H2 made IL-4
• T_H1 made IFN-γ

• 1. nonfunctional CD154 (CD40L) in boys, X- linked hyper-IgM syndrome
• 2. defective CD40
• 3. defective AID (enzyme required for class switch recombination)
• *any defect in CSR --> hyper IgM syndrome

• important antigens don't require helper T cells to make antibody
• these include polysaccharides/lipopolysaccharide components of bacterial cell walls
• responses to TI antigens don't normally produce T cell-derived cytokines, B cells do not undergo Ig class switch
• only IgM is synthesized
• IgM is not expressed on B memory cells, memory B cells DO NOT develop from TI antigens

• 1. Hemophilus influenzae
• 2. Streptococcus pneumonia

• purified capsular polysaccharide from the bacterium conjugated to a protein --> generate T cell epitopes
• allow bacterial components that usually make TI antigens to be recognized by appropriate TCRs, generating a thymus DEPENDENT immune responses in which B cell class switching occurs & memory develops

• kill host cells that have been infected by pathogens, particularly viruses
• commonly referred to as cytotoxic T lymphocytes (CTL) or killer T cells
• play a role in transplantation rejection and the destruction of tumor cells

• CD8+ T cells that have emerged from the thymus and been activated
• occurs via the same two-signal paradigm
• #1 peptide/MHC class I interact w/ TCR
• #2 costimulator signals

activation of virus-specific CD4+ T cells is required for the activation of virus-specific CD8+ T cells

• 1. formation of granules that contain cytotoxic proteins
• 2. expression of the cell surface molecule Fas ligand (FasL or CD95)

• 1. contents of granules in activated CD8+ T cell pass into the target cell --> activate apoptotic mechanisms --> cell death
• 2. interaction of Fas Ligand (CD95) on the CD8+ T cell with Fas on the target cell --> apoptoses the target cell

• perforin: molecule that polymerizes to form ring-like transmembrane pore in target-cell membrane
• granzymes: pass into target cell through perforin made pores & interact with intracellular components to induce apoptosis

• 1. induction of CTLA-4 (CD152) on activated T cell surface
• CTLA-4 (CD152) competes with CD28 to bind to B7 on APC surface
• unlike the CD28-B7 interaction, B7-CTLA-4 transmits a negative signal to the activated T cell, turning off the response
• [CTLA-4 (CD152) can be used in therapies, such as melanoma, to dampen T cell response]

a lymphocyte – a CD4+ or CD8+ T cell or a B cell – that has been stimulated by antigen (in a primary response) and that is activated in a second or subsequent response by the same antigen

an antigen that requires T helper cells to cooperate with B cells to synthesize antibodies

an antigen that does not require T helper cells for B cells to synthesize antibodies

• • Infectious pathogens (TD) – eg. viruses and bacteria
• CD4+ T cells, CD8+ T cells, antibody (IgM, IgG, IgA or IgE) & γδ T cells (especially mycobacteria)
• • “Harmless” TD antigens – eg. vaccine protein
• CD4+ T cells & antibody (IgM, IgG, IgA or IgE)
• • Worms and allergens
• CD4+ T_H2 cells & IgE antibody
• • TI antigens – eg. bacterial polysaccharide
• IgM
• • Tumors
• if immune response is made, predominantly CD8+ T cells (NK, if no MHC class I expression)
• therapies = enhance immune response (by injecting tumor antigens expressed on DC (prostate cancer), or inhibiting turn off signals)