Notes 4.8

I. T-cell Review
a) Maturation in Thymus
>people who lack a thymus (di George Syndrome) have almost no ability to make
antibodies against intracellular pathogens and hard time making antibodies
against extracellular pathogens
b) Antigen Binding
>secondary lymphoid tissues present antigens on MHCs
c) Co-stimulation with B7-family Molecules
>B7-family proteins expressed on surfaces of activated, mature dendritic cells
>act as co-activator of T-cells
—helps bind MHC + antigen and T-cell receptor
—B7 stimulated T-cell to differentiate
d) Migration
>Activated, mature T-cells migrate to B-cell areas of secondary lymphoid tissue
where they present antigen (on T-cells receptor) to B-cells, making B-cells
differentiate into plasma cells
—then, almost all cloned, differentiated T-cells die, few remain as T-memory
cells
II. Subcategories of CD4+ Tcells
*differentiation into categories a result of different cytokine concentrations
a) TH1
>recruit phagocytic cells to deep tissues in response to inflammatory cytokines
b) TH2
>recruit phagocytes, eosinophils, basophils, mast cells to epithelia
c) Follicular T-helper***
>migrate to B-cell follicles, causing B-cells to become plasma cells, secrete
antibody
—this happens in B-cell-containing follicles of secondary lymphoid tissue
d) Memory T-cells –hang out in Go phase, for a very long time
>Memory T-cells left over after a T-cell has:
*recognized an antigen presented by MHC II
*cloned itself a bunch
*stimulated B-cells to produce antibodies specific to its antigen
*and after the infection was over, most of the clones had died off
III. T-cell receptor structure
>arrangement of 8 chains
a) Alpha and beta chains
>actively involved in binding to antigen presented on MHC
*NOT involved in signal transduction
*antigen recognition via dimer of alpha and beta chains
*extremely variable
b) Signaling chains
>involved in signal transduction in activated T-cell
>not variable
IV. T-cell receptor variability
a) Constant Region
>as name implies, doesn’t vary
>part of TCR alpha and beta chains that is attached to membrane
b) Variable region
>composed of alpha and beta chain dimers
>alpha/alpha, beta/beta, alpha/beta
>hypervariable region: where TCR directly interacts w/ antigen
i. complementarity-determining regions
>CDR 1, CDR 2, CDR 3
*CDR 2 mainly binds to MHC (more conserved)
*CDR 1 and 3 bind to complex of MHC + antigen
>CDRs can switch positions on antigen until tightest fit is formed
ii. V (D) J recombination
>same processvariability in TCRs and in immunoglobulins
(like antibodies) from B-cells
>each alpha and beta chain made of 2 or 3 segments: variable,
Joining, and diversity
>many alleles for each segment
> segments recombined randomly
>recombination btw segments because of recombination sequences
Btw segments and RAG proteins (RAG=recombination activation
Genes)
—RAG only expressed in B- and T-cells
1. Alpha-chain pool
>total of 42 V segments, 48 J segments, 2 D segments
2. Beta-chain pool
>total of 43 V segments, 12 J segments, 2 D segments
3. V-J vs. V-D-J combinations
>increases the diversity of TCR
4. Promiscuous dimerization
>whether dimers form based on amino acid sequences of
Segments in respective alpha and beta chains
5. Junctional Diversity
>within hypervariable regions, hypermutable DNA
Sequencesespecially true of regions that connect VD
And J segments
*spec. proteins act at these sites to cause random point
mutations
c) T-cell receptors
>10^13 possible T-cell receptors in one person (more than total # of
T-cells in a person)
i. Sensitivity of TCRs
>~10 MHCs presenting matching antigen to TCR for TCR to
Bind
>any given mature dendritic cell has >1,000,000 MHCs presenting
Different antigens at a time
d) Selection for T-cell receptors
>strong interaction btw T-cell receptor and MHC with antigenclonal
Expansion of T-cell
—T-memory cells
i. Positive selection
>Thymus: selects for:
-TCRs that: strongly bind non-self antigens, weakly bind
Self antigens
ii. Negative Selection
V. Activation of T-cells
>vast majority (99.9%) of T-cells ever made are killed in thymusbinding of self
antigens
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
b) IL-2
c) Homing to secondary lymphoid tissue
d) Proliferation

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