Académique Documents
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Richard T Maziarz, MD
September 13, 2013
Basic concepts
Self vs nonself recognition
Response to danger signals- Inflammation
sterile vs nonsterile
Characteristics of Mamnalian
Immune Response
Self: Nonself Recognition
MHC molecules
MHC class I
HLA-A,B,C
E, F, G, H
Ubiquitous expression
MHC class II
HLA-DR,DP,DQ
DO,DX
Limited expression
Antigenic Diversity
Crystal structure
Immune System
Adaptive immune system vs innate immune
system
Effector cells
Immunologic specificity
Antigen-specific receptors on cell surfaces
T lymphocytes: antigen specific T cell receptor
B lymphocytes: surface IgM or IgM + IgD
T cells
Intrathymic vs Extrathymic differentiation
Thymus differentiation : well ordered pathway cortex--> medulla and out
CD34--> CD34 CD7--> CD2CD7(triple negative)-> CD2CD3 (double negative)--> CD2CD3CD4CD8
(double positive)--> CD2CD3CD4 or CD2CD3CD8
Negative Selection
High affinity TCR for self are deleted following
TCR ligation
0-1
2-10
11-25
26-49
>50
%TE space
93
88
63
45
18
Thymus out
>109
8.8 x 108
6.3 x 108
4.5 x 108
1.8 x 108
Costimulation
TCR and CD28 simultaneous activation leads to T cell proliferation
and target cell death
TCR and CD152 (CTLA4) binding can limit a T cell proliferative
response
The lack of cell surface CD80 and CD86 can lead to T cell
programmed cell death or to induction of peripheral tolerance (e.g.
anergy).
Absence of CD80 on tumor can induce tolerance
Heterotypic antibodies binding CD3 and CD28 can overcome
peripheral tolerance
OKT3 treatment in renal transplants can render T cells refractory to
stimulation
Immunologic Memory:
Antigen exposure--> proliferation and differentiation;
small # of cells may proceed to memory state
Secondary Antigenic Challenge : anamnestic
response
Memory T cells
T-CM:(CCR7+):
IL2, induce DC IL12
T-EM:(CCR7-):
lo IL2, IL4, IL5, IFN-G,
Sallusto, Nature, 1999
Memory/Effector T cells
Effector T cells :
Conventional: Precursor of memory cells?
Hypothesis: Downstream cell after
differentiation of T central memory cell?
Supported by telomere shortening observations
Generation of TREC
CD4= opaque
CD8= open
CD34s=circle
In vitro
Ag stim
HIV
T cell line
Activation of T cell
Render T cells refractory to stimulation
Costimulation (CD3 : CD28)
Targets for therapy of T cell diseases
Genetic defects (SCIDS and others)
Zap 70 deficiency
CD3 gamma or epsilon deletion
Second Signals
T cell sub-subsets
CD4 T cells differentiate into separate
subpopulations of T cell
Th1 are important for cellular responses and resistance
to infection; IL-2, IFN-G, TNF-alpha are produced
Th2 are important for humoral responses and can
increase susceptibility to infection; IL-4, IL-5, Il-6, IL10, IL-13, GM-CSF; can downregulate Th1 responses
Impact of transplantation
conditioning on host immunity
Myeloablative
Immune suppressive
Quantitative and qualitative deficits
Immune reconstitution
Population
% Lymphs
Count/ul %
Total T cells(CD3+)
59.8
316 L
CD3+ CD4+
23.4
124 L
CD3+ CD8+
30.9
163 L
CD3+CD4-CD8-(Doub.neg) 4.8
CD3+CD4+8+(Doub. pos)
0.0
CD4+CD45RO- (naive)
4.6
NKT
6.9
NK cells (CD56+CD3-) 38.4 203
Total B-Cells (CD19+) 0.0
0L
Lymphs count/ul
55-82% 800-3500
20-60% 500-2000
15-30% 300-900
NA
<6%
NA
<2%
NA
8-50%
<3%
5-20% 75-500
5-15% 70-450
Immune reconstitution
% of B-cells % of B-cells
IgD+ CD27- Naive B-cells 0.0 L 58-80%
IgD+ CD27+ Non-switched memory B 0.0 L 7-21%
IgG+ CD27+ Switched, memory B 0.0 L 9-19%
Cellular therapies
LAK + NK-T
IL2/ cytokine ex vivo expanded cell populations
TIL
Tregs
Dendritic cell vaccines-Provenge
CAR-T cells