dynamic programming of cd8 + t cell effector and memory development by innate cytokines david farrar...

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