Lec 44: Adaptive Immunity I Flashcards
Adaptive Immunity
- “acquired”
- specific lymphocyte response to foreign antigen and the development of immunological memory
- response grows with successive exposure
Clonal Selection
specific lymphocytes are activated and proliferated for antibody production against antigen recognized by the antigen receptor
Innate vs Adaptive Immunity
INNATE Specificity: Structures shared by related microbes Diversity: Limited; germline encoded Immunological memory: No Soluble mediators: Complement General cell types: Phagocytes, NK cells
ADAPTIVE Specificity: Antigens Diversity: Unlimited; receptors via VDJ recombination Immunological Memory: Yes Soluble mediators: Antibodies General cell types:Lymphocytes
Cells of the adaptive immune system
o CD4+ T cell – helper T lymphocyte (Th); facilitate adaptive nd innate immune responses
o CD8+ T cell – cytotoxic “killer” T lymphocyte (Tc/CTL); kill infected cells
o B cell – produce antibodies
Mechanics of T Cell Activation
o Signal is initiated if a TCR specifically recognizes the peptide + MHC complex (CD4+ and MHC II/CD8+ and MHC I)
o For naïve T cell, activation requires co-stimulation ~ the co-stimulatory B7 on APC binds to CD28 on the T cell
oTCR recognition of antigen leads to Tyr phosphorylation of CD and ITAMs
o ZAP-70 tyrosine kinase (syk family) is activated by binding to phosphorylated-TCR-ITAM and triggers a cascade of events (increased cytosolic Ca2+) leading to the activation of three transcription factors, NFAT, NF-kB, and AP-1 à IL-2 gene transcription
o IL-2 results in proliferation and effector functions (CD4+ helper T and CD8+ cytotoxic T)
ITAM
(immunotyrosine activation motif) – cytoplasmic tyrosines of TCR that are phosphorylated in response to signaling
Naive CD4+ helper T cell encounter with antigen
o Antigen specific T cells find appropriate APCs w peptide/MHC because there is flow between periphery and secondary lymphoid organs. Dendritic cells pick up antigens in periphery and then enter a lymphatic vessel à enter lymph node. Naïve T cells move from blood to lymph nodes and spleen where they encounter APCs with surface MHC and peptide complexes. Those that encounter specific antigen proliferate and differentiate to effector cells, effector T (short lived) or memory T(long lived) – exit lymph node via efferent lymph.
T cell migration
o Effector and memory T transmigrate into inflamed tissue, while naïve T migrate from blood to lymph nodes.
Memory T Cells
- More rapidly activated than naïve; activation is independent of co-stimulation; generation is fast
- Secondary memory response results in faster recognition and clearance of pathogens
- Long lived – maintained in a resting/scanning state until antigen is encountered
- —- Clinical relevance – memory cells are gradually lost with age, and so you can see reemergence of chicken pox in the elderly (shingles)
Cyclosporin A and FK-506
Immunosuppressive drugs – inhibit T cell proliferation and acquisition of effector functions
o Cyclosporine A/CsA and FK-506/tacrolimus – inhibit calcineurin and then blocks NFAT activation which leads to blocking IL-2 synthesis (inhibits path right after ZAP70)
ZAP70 Deficiency
autosomal recessive, form of severe combined immunodeficiency (SCID), complete lack of CD8+ T cells and CD4+ are non-functional; frequent infections and fatal if no bone marrow transplant (blocks all TCR-dependent signaling)
Rapamycin
immunosuppressive drug
- inhibits signaling from IL-2 receptor so T cell proliferation and effector functions are blocked
T cell mitogens
polyclonal stimulators
- stimulate proliferation
- 3 types: bacterial superantigens, mitogenic lectins, pharmacological activators
Bacterial superantigens (sAg)
- antigens that cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release; generates a massive immune response which is not specific to the SAg thus undermining one of the fundamental strengths of the adaptive immune system
- —–cytokines –> excess Interferon gamma –> macrophage activation –> high levels of proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha –> shock and multiple organ failure
ex: Toxic Shock Syndrome – s. aureus superantigen, TSST-1
ex: S. aureus food poisoning – enterotoxins: SEA, SEB, etc…; most common cause of human food poisoning and potential bioterror weapon
Mitogenic Lectins
plant derived carbohydrate-binding proteins that cross-link T cell surface receptors, mimicking antigen stimulation; does NOT require APCs; ex: ConA, PHA, PWM
-ConA and PHA activate T cells only, and PWM activates T and B
