dynamic programming of cd8 + t cell effector and memory development by innate cytokines david farrar...
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Dynamic Programming of CD8+ T Cell Effector and Memory Development by Innate Cytokines
David Farrar
Department of Immunology
UT Southwestern Medical Center Dallas, TX
Differentiation versus acute response
Proliferation/expansion
Antigen recognitionCostimulationCytokines
Acute effector response
Antigen recognitionCostimulationCytokines
Cytokine secretionLytic activity
DC
CD8+ Cytotoxic T Lymphocytes (CTL)
1. Home to sites of infection2. Secrete inflammatory cytokines: IFN- and TNF-3. Kill infected cells via perforin/granzyme-mediated lysis.
Innate cytokines regulate adaptive immune responses
IL-1IL-6IL-12IL-23TNF-TGF-IFN-
DC
PAMPs
TLRs, NODs, RIG-I/MAVS, etc.
IFN- /a b
IL-12R
IL-12
STAT4
T-bet
Th1/Tc1
IFN-
IFNAR
Proliferation, etc. Antiviral, etc.
Are IL-12 and IFN- redundant signals regulating Th1 development?
&
P-Y
STAT
1
STAT
2
P-Y
IFN- Signaling
STAT
4Y-P
Antiviral Activity
Our Previous Studies:
1. IFN- /a b does not promote Th1 development
2. Enhances IL-2 secretion and development of TCM cells
3. Inhibits Th2 development
IL-12, but not IFN-, regulates IFN- and TNF- expression in human CD8+ T cells
CCR7 and CXCR3 direct T cell traffic in opposite directions
Inflammed tissues:IP-10, MIG
Lymph nodes:CCL19, CCL21
Naïve:CCR7+CXCR3-
Effector:CCR7-CXCR3+
Central Memory:CCR7+CXCR3-
CXCR3+ Effector/EM: -Preferentially traffic to periphery-High cytolytic activity-High effector cytokine expression -Terminally differentiated/poor expansion to recall
CCR7+ Memory/CM: -Preferential lymph node traffic -Low cytolytic activity -Low effector cytokine, high IL-2 -Multi-potent/strong expansion to recall
Induction of effector and memory CTL development by IL-12 and IFN-
Chowdhury, et. al. Blood 2011
CD8+ effector functions are driven by IL-12 and acquired as a function of proliferation
CXCR3+ cells preferentially secrete IFN-
Ramos, et. al. Blood 2009
IL-12 +IFN-
-CD3-CD28
Sort: CD8+ CD45RA+
Sort: Day7CXCR3+/CCR7-
CXCR3-/CCR7+
Examination of recall responses
Ramos, et. al. Blood 2009
Chowdhury, et. al. Blood 2011
Cytokine and lytic activity of TEM cells ex vivo
Effector Memory:CXCR3+/CCR7-IFN-/TNF-Pfp/GrzBLow proliferative capacityTerminally differentiated
IL-12 IFN-
Cytokine-regulated central and effector memory CD8+ T cell development
Central Memory:CXCR3-/CCR7+Low cytokine secretionGrzB hi, Pfp loHigh proliferative capacityAble to generate secondary effectors
What is the mechanism?
How do IL-12 and IFN- co-regulate the development of both TEM and TCM?
Differential cytokine responsiveness?
IL-12 and IFN- promote expression of their own receptors
Ramos, et. al. Blood 2009
Cytokine responsiveness as a function of cell division
Ramos, et. al. Blood 2009
Cytokine responsiveness as a function of cell division
Chowdhury, et. al. Blood 2011
Distinct gene expression patterns are acquired as a function of cytokine responsiveness and proliferation
Chowdhury, et. al. Blood 2011
Unique gene signatures of TEM and TCM
Chowdhury, et. al. Blood 2011
Identification of IL-12-induced genes that are stably expressed in TEM in vivo
Dynamic programming of TEM and TCM cells
IL-1
2
SignalStrength
IFNAR2
IL-12R2TCM TEM
Effector Memory
IFN
-
Central MemoryRecall
Jon Huber, Navin Chowdhury,Didem Agac, Leo Estrada,Ann-Marie Schaefer,Sarah Gonzales, Hilario Ramos,Ann Davis
Jim Forman, Ph.D. Becky Gruchalla, M.D., Ph.D.Michelle Gill, M.D., Ph.D.
Amnis/Millipore:Tad George, Ph.D.
Flow Cytometry Core, UTSW:Angela Mobley, M.S.Christina Nguyen, B.S.
Funding:NIH, NIAIDCrystal Charity Ball
Acknowledgements