immune sensing of latent cytomegalovirus reactivation: impact on immune senescence?
DESCRIPTION
Institute for Virology. Immune Sensing of Latent Cytomegalovirus Reactivation: Impact on Immune Senescence?. Molecular Virology Lab. Immunology Lab. Cytomegalic Inclusion Disease (CID): a disease of the immunocompromised. Congenital infection (in the US) Cases per annum:40,000 - PowerPoint PPT PresentationTRANSCRIPT
Immune Sensing of Latent Cytomegalovirus Reactivation:Immune Sensing of Latent Cytomegalovirus Reactivation:Impact on Immune Senescence?Impact on Immune Senescence?
Molecular Virology Lab Immunology Lab
Institute for Virology
Cytomegalic Inclusion Disease (CID):a disease of the immunocompromised
Courtesy of G.JahnInstitute of Medical Virology
TuebingenJahn et al., Dtsch. Med. Wochenschrift, 1988
Congenital infection (in the US)
Cases per annum: 40,000Asymptomatic at birth: 36,000
5,400 Neurol. sequelaeSymptomatic at birth: 4,000
3,600 Neurol. sequelae 400 Fatal cases
CMV vaccine is 1 out of 7 ranked in level 1 out of 26 candidate vaccines included in the study
Annual gain of18,000 - 70,000 QALYs
Annual saving to the health systemUS $ 1.1 billion - 4.0 billion
Transplantation-associated (in the US)
Cases per annum: 2,800Moderate disease: 1,200Severe disease: 1,600
160 Fatal cases
IOM study: Vaccines for the 21st century
Immune senescence:A new indication for a CMV vaccine?
People aged 65 and older in the US ~ 40 millionCarriers of latent CMV ~ 30 million
Holtappels et al., JVI, 1998Podlech et al., JVI, 2000
Recipient
mCMV6 Gy
BMC
DonorBALB/c BALB/c
~
Immune surveillance of CMV in the murine BMT model
months
LungsAcute phase Latency
1
Viru
s
CD
8 T
cells
105
months
LungsAcute phase Latency
1
Viru
s
CD
8 T
cells
105
Recipient
mCMV6 Gy
BMC
DonorBALB/c BALB/c
~
Podlech et al., JVl, 2000
Inflammatory focus
Red staining of intranuclear IE1 proteinBlack staining of CD8 T cells
Control of acute CMV infection in the lungs
Podlech et al., JVI, 2000Holtappels et al., JVI, 1998; 2000
Recipient
mCMV6 Gy
BALB/c
~
Effector CD8 T cells• Activated phenotype CD62Llow
• Secrete IFN- • Lyse infected target cellsProtection upon adoptive transfer
Control of acute CMV infection in the lungs
CD8 T cell
months
LungsAcute phase Latency
1
Viru
s
CD
8 T
cells
105
Recipient
mCMV6 Gy
BMC
DonorBALB/c BALB/c
~
Effector-memory CD8 T cells
• Activated phenotype CD62Llow
• Secrete IFN- • Protect upon adoptive transfer
Persistence of protective CD8 T cell infiltrates during latency
~Episome
The immunodominant IE1 peptide of murine CMV
ORF Phase Sequence Restriction Reference
m123 (ie1) IE 168YPHFMPTNL176 Ld Reddehase, Rothbard, and Koszinowski, Nature, 1989
IFN- + IFN-
ERAAP
Presentation
ER
Golgi
CD8+
T cell
TAP
TCR
IE1
Processing andpresentation
of the IE1 peptide
Processing
For a review, see:Reddehase,Nature Rev. Immunol., 2002
Constitutiveproteasome
Immuno-proteasome
LungsAcute phase Latency
1V
irus
CD
8 T
cells
105
Enrichment of IE1 peptide-specific CD8 T cells during latency
1
3
M84
m18
m04
M83
m12
3/IE
1
4
5
M45
% E
LIS
PO
T-re
activ
e C
D8
T ce
lls
2
1
3
M84
m18
m04
M83
m12
3/IE
1
4
5
M45
%
ELI
SP
OT-
reac
tive
CD
8 T
cells
2
30.00012.000 3.000
60.000
mo
Holtappels et al.,J.Virol., 2000
Major Immediate-Early (MIE)region of mCMV
IE1 specific RT-PCR
P1/3 enhancer
1
ie1/3 transcription unit
M122 m123
Differential splicing
2345
235 1
234 1IE1 mRNA
IE3 mRNA
TFBS
Activation
What is the motor that drives the selective expansionof the IE1-specific CD8 T cells?
Selective and stochastic IE1gene expression during latency
Signal
Receptor
TF
IE1 specific RT-PCR
What is the motor that drives the selective expansionof the IE1 specific CD8 T cells?
Selective and stochastic IE1gene expression during latency
P1/3 enhancer
1
ie1/3 transcription unit
M122 m123
Differential splicing
2345
235 1
234 1IE1 mRNA
IE3 mRNA
TFBS
Activation
Signal
Receptor
TF
Major Immediate-Early (MIE)region of mCMV
IE1 specific RT-PCR
What is the motor that drives the selective expansionof the IE1 specific CD8 T cells?
Selective and stochastic IE1gene expression during latency
P1/3 enhancer
1
ie1/3 transcription unit
M122 m123
Differential splicing
2345
235 1
234 1IE1 mRNA
IE3 mRNA
TFBS
Activation
Signal
Receptor
TF
Major Immediate-Early (MIE)region of mCMV
IE1 specific RT-PCR
What is the motor that drives the selective expansionof the IE1 specific CD8 T cells?
Selective and stochastic IE1gene expression during latency
P1/3 enhancer
1
ie1/3 transcription unit
M122 m123
Differential splicing
2345
235 1
234 1IE1 mRNA
IE3 mRNA
TFBS
Activation
Signal
Receptor
TF
Major Immediate-Early (MIE)region of mCMV
Poisson distribution analysisof variegated gene expression
What is the motor that drives the selective expansionof the IE1 specific CD8 T cells?
Selective and stochastic IE1gene expression during latency
P1/3 enhancer
1
ie1/3 transcription unit
M122 m123
Differential splicing
2345
235 1
234 1IE1 mRNA
IE3 mRNA
TFBS
Activation
Signal
Receptor
TF
Major Immediate-Early (MIE)region of mCMV
Kurz et al., JVI, 1999Grzimek et al., JVI, 2001Simon et al., JVI, 2005
Generation of recombinant CMV with a point mutation in thecodon of the C-terminal MHC anchor residue of the IE1 peptide
PYH
FM
PT
N A
GCALPY
HF
M PTN
CTA
234IE1
WT and revertant MHC class-I anchor mutant
L176A
A176L
Elimination of IE1 antigenicity enhances the frequencyof latency-associated IE1 transcription
Revertant Mutant
27
10
50
100 105
Inci
denc
e of
IE1
trans
crip
tion*
~
~
21
36
84
131
150
* 5 lungs
Simon et al., in preparation
IE1
Desilencing and immune sensing hypothesis
IE1-specificCD8 T cell
Desilencing and immune sensing hypothesis
IE1
Desilencing and immune sensing hypothesis IE1-specificCD8 T cell
IE1-specificCD8 T cell
Desilencing and immune sensing hypothesis
IE1
Desilencing and immune sensing hypothesis IE1-specificCD8 T cell
IE1-specificCD8 T cell
Effector function
Desilencing and immune sensing hypothesis
Multiple checkpoints for immune sensing
Open viral chromatin structure at all essential loci
Abrogation of immune sensing by immunosuppression
MIE locus latency Stages of transcriptional reactivation Recurrence
IE1
anti-IE1 anti-X1 anti-Xn
Immunosuppression
MIE Locus
~
Conditions for virus recurrence:
How could latency-associated CMV gene expression contribute to immune senescence?
1. Cellular aging of clonotypic memory cells by a high number of cell divisions
2. Misallocation of immune system resources by clonal expansion of memory CD8 T cells specific for a single pathogen