Cytokines and T cell Signaling - University of Texas at El...

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Cytokines and T cell Signaling

CHARLOTTE VINES, [email protected] Sciences Bldg. 4.124

Overview of TCR signaling

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Brownlie & Zamoyska, Nature Review Immunology; 2013; Vol 13 p257-269



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Spatial temporal control of

LAT


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LAT



LAT


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Function of PLC

� Generates IP3 to induce release of Ca2+ from the

endoplasmic reticulum into the cytoplasm

� Ca2+ works with DAG to activate PKC

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Function of PLC

Biophysical properties of the

Calcium Release Activated

Channel (CRAC)

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Calcium signaling in T cells

Once activated, how is expansion of T cell subsets regulated?

Abbas, Lichtman, Pillai, Cellular and Molecular Immunology, 7th edition. Copyright 2012 by Saunders

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JAK-STAT

� Janus kinase-signal transducer and activator of

transcription

� STAT (Signal Transducer and Activator of

Transcription)

Th1 Differentiation

R&D SIGNALING

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Roles of TNF in T cells

O’Shea, Nature Review Immunology; 2002; Vol 2 p37-45



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Th1 Differentiation

R&D SIGNALING

Cytokines and helper T cells


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Inflammatory Cytokines?

� Pro-Inflammatory?

� IL-2

� IFN-γ

� TNF-α

� Anti-Inflammatory?

� IL4

� IL10

� TGF-β

JAK/STAT Pathway

IFNAR1

IFNAR2

P

PP

P

PP

P

P

P

P

PP

PP

P

STAT1

STATs

STATs

STAT1STAT5

STAT3UbUb

SOCS

Rbx1

SUMO

SUMO

SUMO

IRF9

P

P

P

P

P

STATs

STAT1

STAT1

P

P

P

P

P

P P

PPP

STATIP

CTFsP

Cofactors

STATs

Ub

P

P

P

PP

AktPathway

P

P

STATs

P

STATs

RAN

c-Myc

JAKs

STATs

IFN-Inducible

Gene Expression

IFN-Inducible

Gene Expression

Nml, SOCS, BCL-XL-, p21, Myc, Nos2,

Gene Expression

Nml, SOCS, BCL-XL-, p21, Myc, Nos2,

Gene Expression

GeneExpressionGene

Expression

GASGAS

ISREISRE

STAT5

Elongin-C

ERKs

PIAS

ST

AT

s

JAKs

STAT2

PI3K

SOSSHP2P

GrowthHormonesGrowth

Hormones

SHP1

CytokinesCytokines

CytokineReceptorCytokineReceptorI

FN

γγγγR1

IFN

γγγγR2

JAK2TYK2

GPCRLigands

IRF9STAM

P

Akt

SOCS

Raf

MEK

Proteasome

STATs

STAT3

STAT1STATs

SOCS

P

JAK

JAKs

JAKsJAK2

Ras

Ubc9

JAK Degradation

KPNA1

IRF9

2009ProteinLounge.com

2009ProteinLounge.com

C

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Pro-survival Cytokines?

� Pro-survival?

� IL-7-survival by not cell cycle entry

� IL-4-survival by not cell cycle entry

� IL-2

SURVIVAL VS PROLIFERATION

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Traditional view of Cytokines


Revised view of Cytokines


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Skewing of the immune

response

� Th1

� Th2

� Th17

� Th0

Expansion of Th1 cell Cells


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Yes, but how do we turn off the

signaling?

SOCS

� 8 family members Suppressor of cytokine signaling

� Induced by cytokine

� Negative feedback loop in the cytokine induced JAK-STAT pathway

� Likely function of E3 ubiquitin ligases and mediate protein degradation of signaling complexes

� SOCS interacts with the MTOC

� Interacts directly through kinase inhibitory region (KIR) to inhibit JAK2-mediated phosphorylation of STAT1

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SOCS

Yoshimura, Naka, Kubo, Nature Review Immunology Vol 7 June 2007

SOCS


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Role of SOCS in T cell

development

May prevent inadvertent signaling from

pro-survival cytokines and harmful

effects of IFN-γYoshimura, Naka, Kubo, Nature Review Immunology Vol 7 June 2007


regulation


Th1 5-fold higher

levels of SOCS1

Th2 23-fold higher

levels of SOCS3

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regulation


Th1 5-fold higher

levels of SOCS1

Th2 23-fold higher

levels of SOCS3

What happens when signals

wane?

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Cytokine Regulation of

metabolism-when growth

factors are limited

Invitrogen

� Autophagy

� Breakdown of

intracellular

constituents to

generate ATP

Development of Memory T

cells


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Development of Memory T

cells


Disorders affecting

lymphocytesMarch 18, 2014Charlotte M. Vines, Ph.D.

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Objectives

� Non malignant disorders

� Leukocyte adhesion deficiency type II

� Bare lymphocyte syndrome

� Bruton’s tyrosine kinase

� Malignant disorders

Thymus

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Thymus

CD8

CD

4

SP CD4+ DP

SP CD8+DN

Total thymocytes

Lymph Node

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Spleen

Adaptive immune response-Lymphocytes

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Adaptive Immune response

Diseases due to adaptive immune

deficiencies

� X-linked agammaglobulinemia-BTK

� ADA Deficiency

� DiGeorge Syndrome

� Common gamma chain deficiency

� BLSII

� RAG1 or RAG2 deficiencies (missense= Omenn Syndrome)

� Null mutation in RAG1 or RAG2 (SCID)

� Note SCID is fatal early in life unless immune system is reconstituted-� Bone marrow transplants� IVIG (B cell defects)� Treat patients with antibiotics as needed

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Antibody locus

Diseases due to adaptive immune

deficiencies –B-cells

� Hyper IgM

� Hyper IgE (Job’s)

� Selective IgA deficiency

� Common variable immunodeficiency

� Wiskott Aldrich Syndrome

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Diseases in infants

� Erythroblastosis fetalis

� Transient hypogammaglobulinemia of infancy

� Neonatal Neutropenia

Zinkernagel R. N Engl J Med 2001;345:1331-1335

Protective Effect of Maternal Antibodies in Serum and Milk

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Autoimmune Diseases

� Rheumatoid arthritis

� Systemic Lupus Erythematosus

� Goodpasture’s syndrome

� Myesthenia gravis

Cancer

� Multiple myeloma

� Leukemias

� Lymphomas

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Infection

� HIV-Acquired immune deficiency

� Septic shock

� Toxic shock

� Crohn’s

Transplant

� Hyperacute rejection (immediate)

� Acute rejection (weeks)

� Chronic rejection (months- years)

� Graft-vs-host disease

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Which of these patients has normal peripheral blood T

lymphocytes?

Case

Which of these profiles would you expect in a patient with

HIV/AIDS if you examined the peripheral blood T lymphocytes?

Case

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PAPER FOR THURSDAY

� Simultaneous zinc-finger nuclease editing of the

HIV coreceptors ccr5 and cxcr4 protects CD4+ T

cells from HIV-1 infection

� 2014 123: 61-69

� W. Doms

� Danet-Desnoyers, James L. Riley, Phillip D.

Gregory, C

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