Immunoregulation Flashcards
Activation and Differentiation of Naïve TH cells
Activation and differentiation of naïve TH cells requires three independent signals delivered by the same APC
Signal 1: ligation of TcR (and CD4 or CD8 co-receptors) to MHC-peptide on APC
Signal 2: co-stimulatory surface molecules such as B7 (B7.1 = CD80 and B7.2 = CD86) on APC binding with CD28 on T cells
Signal 3: cytokines from the APC or tissue environment at the time of antigen recognition
Regulation of Immune Responses by CD4+ T cell Subset-Derived Cytokines
Differential release of cytokines by CD4+ T cell subsets control:
Humoral vs. Cell-mediated immunity
IFN-g producing TH1 cells (promoting CMI and opsonizing Ig) and IL-4 producing TH2 cells (promoting nonopsonic IgG, IgA, IgE) are counter-regulatory cells (mutually antagonistic or suppressive).
Tolerance to autoantigens or nonself antigens (commensal microbes, pollens, food antigens)
Induced regulatory T cells (Treg) exhibit immunosuppressive (regulatory) function after unique stimulatory conditions
Natural suppressor CD4+CD25+ T cells (nTreg) develop in the thymus.
Dendritic Cell Control of Pathogen-driven T cell Polarization
Once immature dendritic cell sees Ag, it matures based on the TLR response to PAMPs and tissue factors
Then the dendritic cell secretes cytokines and co-stimulatory factors that influence the determination of which T helper subsets are made (Th1, Th2, Th17, or T reg)
TH1
Secretes IFN gamma, TNF alpha, IL-2, and IL-6
Promotes CMI and opsonizing Ig
INF gamma promotes:
macrophage activation and IgG production
response to intracellular microbes
role in autoimmune disease and tissue damage with chronic infections
If TH1 cell presenting to macrophage via INF gamma, then causes macrophages activation and enhanced microbial killing If TH1 is presenting to B cell via IFN gamma, then this promotes the B cell via INF gamma to class switch from IgM to IgG and complement binding and opsonizing
TH2
Secretes IL-4, IL-5, IL-10, and IL-13
Promotes non-opsonizing IgG, IgA, and IgE
IL-4, IL-5, and IL-13 promotes:
mast cell, macrophage, and eosinophil activation
IgE production
response to Helminthic parasites and allergic diseases
IL-4 to B cells = IgG to IgE switching
IL-4, IL-13 = intestinal mucus secretion and peristalsis; alternative macrophage activation for enhanced fibrosis/tissue repair
IL-5 = eosinophil activation
TH17
Secretes IL-17A, IL-17F, TNF-alpha, and IL-22
Promotes:
neutrophilic and monocytic inflammation
defense in extracellular bacteria and fungi
role in autoimmune and inflammatory diseases
IL-17 = activates leukocytes and tissue cells to produce chemokines, TNF, IL-1, IL-6, and CSF to cause inflammation and neutrophil response as well as antimicrobial peptides IL-22 = activates tissue cells for antimicrobial peptides and increase barrier function
Treg
Secretes IL-10 and TGF beta Exhibits immunosuppressive (regulatory) functions Induced by non-infectious agents and Treg turns off the immune system and maintains peripheral tolerance to prevent unnecessary chronic/acute inflammation
Th0 Differentiation
IL-12, IFN gamma = TH1
IL-4, IL-2 = TH2
TGF beta, IL-6 = TH17
TGF beta, IL-2 = Treg
*signals are from dendritic cells to Th0 to develop into these respective subsets of T helper cells
Absence of Infection Signals
In absence of infection (absence of IFNg or IL-12), high TGFb promotes differentiation of Treg that suppress Th1 or Th2 responses to normally presented self antigens via Treg release of TGFb and /or IL-10.
Early Infection Signals
Early in infection, high IL-6 and IL-23 release combine with TGFb signals to induce TH17 differentiation. TH17 cells secrete IL-17 (induce epithelial, endothelial, fibroblast release of chemokines that promotes neutrophil recruitment) and IL-22 that induces b-defensin production.
Late Infection Signals
Pathogen-induced cytokines (via TLR activation) predominating in later stages of infections drive differentiation of Th1 and Th2 subsets.
Common extracellular bacteria: dendritic cell pick up these it will release IL-12 and interact with NKC and produce INF gamma = indicate inflammatory stimuli and T cell will make TH1, which major product is INF gamma to continue opsonization and inflammatory responses
There are certain types of microbes and allergens that may produce high levels of IL-4 production to make TH2, which make IgE (for parasites and hypersensitivity/ allergic reactions)
Parasitic Worms
Worms: can stimulate NKTC that have surface markers that are like NKC and have T cell receptors, and recognize glycolipids in local tissues and make lots of IL-4 and this causes T cells to go to TH2 TH2 secretes IL-4, which causes Ig class switching of B cells to E class to promote cytotoxic reactions to parasites like mechs to expel the worms and also hypersensitivity reactions
Control of Activated T cells
CTLA-4 expression replaces CD28 during later stages of T cell activation to provide a negative signal for further T cell expansion
Activation-induced cell death (AICD). Activated T cells (both CD4+ and CD8+) express Fas and/or FasL during the later stages of immune response when antigen diminishes. FasL-Fas interactions induce apoptosis to eliminate most of the clonally expanded, specific effector T cells that are no longer needed. Memory T cells (Fas-) are spared
If lymphocytes kept proliferating, it would be bad so Ag driven process = lymphoproliferative diseases otherwise
Regulation of Immune Responses (IR) by Antigen Concentration
Too low or too high a dose of antigen will be non-immunogenic or toleragenic respectively.
Continuing IR are antigen-driven and decline in parallel with antigen concentration (antigens, costimulators, and cytokines provide survival signals that prevent apoptotic pathways)
Soluble and readily degraded and excreted antigens are poorly immunogenic
Aggregated or persistent antigens are more immunogenic
Some “adjuvants” promote immunogenicity of materials by prolonging immunogen halflife in vivo
Antibody Feedback Inhibition and Anti-Idiotype Ab
Antibody feedback inhibition of IR
B cell binding of antigen-antibody complexes via BCR and FcgRIIB-1 simultaneously delivers a negative signal to B cells
BCR signaling is inhibited by FcgRIIB-1 associated ITIMS (immunoreceptor tyrosine-based inhibitory motifs)
Once you made many Ab/ complexes, it provides B cell with negative feedback to turn off; B cells also have Fc receptors and immune complexes can cross link and send negative signal
Anti-idiotype antibody (anti-antigen receptor)
anti-idiotype antibody mimics the 3-D shape of the original antigen (an internal image of external antigen) and can positively or negatively regulate lymphocyte activation.
