April 15 Notes

I. Activation of T-cells
>vast majority (99.9%) of T-cells ever made are killed in thymusbinding of self
a) Co-receptors
*strengthen interaction btw T-cell and dendritic cell
*induce signal transduction, leading to activation of T-cell
i. CD4 and CD8
*interact directly with MHC
ii. CD28 and B7
*B7—expressed by mature, activated dendritic cells; interacts with CD28 on T-cells
*CD28 binding to B7signal transductionactivation of T-cells
1. NF-kappa-B signaling
*activated by TCR-MHC interaction and by CD28-B7
b) IL-2
*NF-kappa –B activates transcription/translation of IL-2 and IL-2
*IL-2 major growth factor for T-cells (thisclonal expansion, IL-2
stimulates T-cell division)
c) Homing to secondary lymphoid tissue
*CCR7 on activated T-cell surface interacts w/ CCL2 in lymph nodes
endothelial cells
*this allows T-cell diapedesis through lymph node venule to get to interior
of lymph node
d) Proliferation
*CD4+ T-cells multiply to ~10000 times starting # in 24 hr after activation
*CD8+ T-cells ~50000x
*CTLA4 expression turned on after IL-2, IL-2 R expression
-counter growth factor, stopping clonal expansion in T-cells
-turned on ~24 hrs

I. Differentiation of T-cell subtypes
*CD8+ T-cell development a result of interactions w/ CD4+ T-cells and IL-12
*all differentiation in T-cells (even irreversible changes) from changes in gene
expression, not change to DNA sequence of cell
II. CD4+ T-cells
a) TH1
*secreted IFN-gamma
*IFN-gamma leads to the activation of natural killer cells, CD8+ toxic
T-cells, macrophages; can also induce B-cells to make pro-phagocytic
antibodies (IgG)
—kind of antibody that can stimulate classical complement pathway
b) TH2
*secrete cytokines that:
—activate mast cells , basophils, eosinophils
*expulsive responses
*release antimicrobial content of granules
—activate B-cells to release “barrier antibodies” (IgE)
**not good opsonins, but cover microbe, disable function of
c) TFH
interact w/ B-cells in secondary lymphoid tissue
d) TH17
*secretes IL-17
*a cytokine which activates neutraphils, attracts to site of inflammation
III. CD8+ T-cells
*mechanisms of toxicity to intracellular-pathogen infected cells:
a. Perforins and granenzymes (cytotoxic chemicals) stored in granules: released to act upon target cell when MHC-TCR interaction occurs
*CD8+ T-cells protected from own cytotoxic chemicals by cathespin B lined granules that block the effects of the cytotoxic chemicals after release.
b. Produce Fas ligand in cell membrane- binding of Fas ligand with Fas ligand receptor on target cell stimulates pathway for apoptosis
IV. T-memory cells
*naive T-cells maintained by IL-7 (over time, ability to produce IL-7 receptor is reduced= reduced number of naive T-cells that exist)
*memory T-cells also maintained by IL-7
a. CD4+memory T-Cells
*maintained by IL-7 and antigen-MHC-TCR interactions
*can survive for about a decade
b. CD8+memory T-Cells
*longer lived than CD4+memory T-Cells, up to 30-40 yrs w/o stimulation by antigen.
*also maintained by IL-7
*important for defense against very mutation-prone viruses (like the flu)
*can go through additional clonal expansion in response to renewed stimulation with antigen (especially w/ latent viruses)

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