T Helper and Memory Cells 2016

8/18/2019 T Helper and Memory Cells 2016

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Effector and memory T cells

I

Assoc. Prof Mark Wright

Dept. of Immunology, Monash University

[email protected]


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Reading for this lecture

•

Janeway, relevant sections of Chapters 9,11 and 14

• Abbas, chapter 13

• For a simple review on the Th1/Th2

paradigm: Romagnani. Immunology Today.1997. 18: 263


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Learning objectives….. thenext 2 lectures…….

•

Understand the role that effector T cells play inthe context of the adaptive immune response•

Describe the specialised functions of 3 of themajor types of effector T cells:– Th1 cells

–

Th2 cells– Th17 cells• Treg cells (you’ll get most of this in a later lecture from Magda Plebanski)• Tfh cells (you’ll hear more from Fabienne Mackay)

• Understand the concepts involved inimmunoregulation and Th1/Th2 balance

•

Understand the unique properties of memory Tcells– Homing– Lower threshold for activation– heterogeneity


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• Lecture 1– Focus on Th1 vs Th2 cells

•

Lecture 2– Th17 cells – how does this effect the

Th1/Th2 paradigm?

– Memory T cells


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Proliferating T cells differentiate intoeffector T cells that drive the adaptive

immune response


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•

T cell expansion anddifferentiation occurswithin lymphoid organs

•

DifferentiatedEffector T cells willthen migrate to theperiphery to the siteof inflammation

The anatomy of adaptive cellularimmunity


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The function of effector

cells is determined by thearray of effector moleculesthey produce

• Effector CD8 T cells produce cytotoxins– Perforin and granzymes

• Effector CD4 T cells produce cytokines–

IL-4, IL-5, IL-13, IFN-!, IL-17


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CD4 T cells• Orchestrate the functional activity of

innate and adaptive immune systems• They do this via the differential secretion

of cytokines which “help” other arms ofthe immune response

•

CD4 effector cells are heterogeneous -CD4 T cells can differentiate into at least5 different types of effector cells–

Th1, Th2, Th17, Tfh–

Treg

•

Their differentiation is also directed bycytokines


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Effector T cells


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Lets take a short trip back in time to2004, when Th cells were simpler…….

•

Th1 and Th2 cells werefirst identified in thelate 80s

•

Treg cells were re-discovered in the 90s

•

Th17 cells werediscovered in 2005…

• Tfh….2008/9


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Thelper 1 cells promote cell

mediated immunity• The major role of

Th1 cells is tosecrete IFN-!

•

A major activity ofIFN-! is to activatemacrophages (M1macrophages) andmake them efficientkillers ofintracellularpathogens


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Changes induced in activated

macrophages•

Increase production ofcytokines:– TNF-", IL-1 (pro-

inflammatory)

–

IL-12, IFN-!

•

This inducesproduction ofantimicrobial agentssuch as NO and O2

-

•

Increased expressionof MHC andcostimulatorymolecules


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Th1 biology a more complexversion!!

• IFN-! also induces isotype switching toIgG2a and 2c (mouse)


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Th1 Differentiation• Which effector cell

developmental pathway anuncommitted CD4 T cell (Th0cell) “chooses” is determinedby the cytokine milieu duringT cell activation

• IFN-! can “self-amplify” thedifferentiation of CD4 T cellsinto Th1 cells

• IL-12 is secreted by APC anddrives the switch from anundifferentiated Th cell

(Th0) to a Th1 cell

• IFN-! is made by NK cells andTh1 cells; IL-12 by APC


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The inflammation induced byTh1 cells can cause pathology

• Th1 cells can induceType IV sensitivity

reactions (Delayedtype hypersensitivity)


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Th1 cells can causepathology in

infection


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Th2 cells promote humoral

immunity•

Th2 cells secrete IL-4, acytokine criticallyimportant in promoting Bcell activation

•

IL-4 will drive isotypeswitching towards humanIgG4 (mouse IgG1) andIgE

•

IL-4 also is “self-

amplifying” and promotesdifferentiation of Th0cells into Th2


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A more complex version ofTh2 biology

•

Th2 cells also secrete IL-5,and IL-13.

• IL-5 mobilises and activatesEosinophils.

• IL-13 can modify macrophage

activation, promote epithelialcell repair, smooth musclecontraction and mucusproduction

• IgE, mast cells and eosinophilsare all critically importantcomponents of the immunedefence against helminths….


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Th2 cells protect us from helminths

Helminths areToo big for

phagocytosis


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Antibody DependentCytotoxicity

Worm displaying antigens

IgE

Fc receptor for IgE

Mast cell or Eosinophil

• Upon crosslinking theirFc$ receptor, Mast cells

and Eosinophils degranulate andkill helminths• IgE and eosinophil responsesAre controlled by Th2 cells


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Eosinophils attacking

schistosome larvae


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Weep and Sweep Response -parasite expulsion

•

IL-4 and IL-13:–

increase smooth musclecontraction

–

Increase intestinal

permeability– Increase mucus

secretion by gobletcells

– Increase sensitivity ofthese cells to mast cell

mediators


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Th2 cells can also alternativelyactivate macrophages, through

IL-4 and IL-13• M2 macrophages:

– Produce arginase

rather theninducible nitricoxide sythetase

– Producecollagen..

–

Specialised intissue repair


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Th2 cells can cause

pathology• Type 1 or immediate

hypersensitivity responsesoccur minutes to hours after

re-exposure to antigen


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Th2 cellscause atopic

disease• Exposure to antigen

leads to theinduction of Th2

cells and theproduction of IgE

• Re-exposure toantigen leads to mast

cell degranulation,histamine release,cytokine production


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Th1 vs Th2 a summary

•

Th1 produce IFN! andpromote cellularimmunity

•

Th2 produce IL-4 andpromote humoralimmunity

•

Th1 and Th2 arepreceded byundifferentiated Th0

cells.


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Cytokines determine Thdifferentiation


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Development of Th1 and Th2 subsets

•

IL-12 and IFN-! drives

Th1 differentiation;major source early areNK cells

•

Tbet is a transcriptionfactor that is amaster regulator forTh1 production

•

IL-4 drives Th2production; majorsource early are NKTcells

•

GATA-3 is thetranscription factormaster regulator forTh2 production


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Th1/Th2 balance affectsinflammatory diseases

• T-bet is the mastertranscription factorthat promotes Th1cells

•

T-bet-/- mice have adysregulated Th1/Th2 balance andspontaneously

develop an asthmalike disease


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Immunological diseases were largelyexplained by Th1/Th2 dysregulation…

• excess Th1 responses are implicated in causing autoimmunedisease

Th1

Th1

Th2

Th2

Auto-immunity


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The incidence of EastGerman atopic disease

From Heinrick et al. European J. Epidemiology 14:241 1998


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Hygienehypothesis

•

Genetics plusenvironment causeatopic disease

• The original theorystated “un-hygienic” exposure to pathogensdrives Th1 responsesand suppresses Th2responses

•

Almost certainly toosimplistic…….

•

Cannot explain the riseof Autoimmune diseases


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So what do Tregs do?

•

Tregs inhibit BOTH Th1 and Th2 responses

Th1 Th2

Th1 Th2

Tregs

More details from Magda Plebanski!.

l


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Counter-regulationhypothesis

• Genetics plus environmentcause atopic disease

• “un-hygienic” exposure to

all types of pathogensdrives regulatory responses(Tregs: IL-10 and TGF-b)which suppresses BOTHTh2-driven atopic diseaseand Th1 drivenautoimmunity

T Helper and Memory Cells 2016

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