13 14 immunology leitenberg tcellimmunity 01-27-14

8/13/2019 13 14 Immunology Leitenberg TCellImmunity 01-27-14

1/8

January 27, 2014

3:00-4:00

Dr. Leitenberg

Notetaker #22

T cell Immunity

Slide #38/39: So this is a nie su!!ary s"ie that he"$s you %igure out &hat the ro"e is o%

'arious i%%erent e%%etor e""s.

Slide #40: So &hat o &e &ant to kno& is &hat regu"ates ( e"" e%%etor e'e"o$!ent) *"inia""y

this is i!$ortant beause you &ant to be ab"e to target i%%erent ar!s o% the i!!une res$onse.

Slide #40: +t in'o"'es a"terations in the antigen ree$tor signa"ing $ath&ay, a"terations in the

ty$es o% osti!u"atory !o"eu"es. + ta"ke about *D2 a "ot but +! a"so ski$$ing a "ot o% other

osti!u"atory !o"eu"es that you ont nee to kno& about. n then there are ytokines, an

the ty$e o% ytokine &i"" a%%et the outo!e o% ( e"" i%%erentiation.

Slide #42: So this is a su!!ary o% &hat + /ust sai. Signa"ing through ( e"" antigen ree$tor,

signa"ing through osti!u"atory !o"eu"es, ytokines, an theres other things you nee to think

about "ike ho& so!e e""s are $reo!!itte to oing ertain things. So &e'e a"reay ta"ke

about ho& &hen ( e""s e'e"o$ in the thy!us they beo!e either CD4or CD8e""s. n its

true that *D4 e""s are !ore "ike"y to beo!e a T helpere"", &hereas *D e""s are !ore "ike"y

to e'e"o$ ytotoi e%%etor %untion. So theres so!e $re$rogra!!ing$reo!!it!ent

in'o"'e here. nother thing that goes a"ong &ith this is &here the e"" is ati'ate !ay

in%"uene &hat ha$$ens to it. eause the !iro en'iron!ent its ati'ate in eter!ines &hat

ytokines its e$ose to, &hat ty$es o% antigen $resenting e""s its e$ose to, &hih in turn

eter!ines &hat ty$es o% osti!u"atory !o"eu"es its e$ose to. So i% you ha'e e""s that are

being ati'ate in the !uosa" assoiate "y!$hoi tissue, they !ay be e$ose to one set o%signa"s that are i%%erent than the signa"s behin your knee in the $o$"itea" "y!$h noes.

Slide #43: So "ets ta"k a "itt"e bit !ore about the *D4 e%%etor e"" subsets. "" o% these e""s are

haraterie by &hat ytokines they !ake. So here you an see TH1e""s are e%%etor e""s

that !ake +N 5 'ery &e"". n one o% the onse6uenes o% !aking +N-5 'ery &e"" is that they

ati'ate !aro$hages so that !aro$hages are better ab"e to ki"" the !irobes they eat. TH2

e""s !ake i%%erent ytokines "ike IL4, an IL!that ati'ates eosino$hi"s, !ay $otentiate !ast

e"" ati'ation, he"$s e""s !ake +g. n &e"" "earn that I"engages &ith !ast e"" ree$tors

to ati'ate !ast e""s, an a"so these e""s e'e"o$ to !ake i%%erent i!!unog"obu"in

isoty$es. ( %o""iu"ar he"$er e""s o a si!i"ar thing. (hey a"so he"$ e""s "ona""y e$an in

ger!ina" enters, an e'e"o$ into antiboy sereting e""s. TH1$e""s see! to !ake ytokines

IL1$&hih interats &ith onneti'e tissue e""s "ike %ibrob"asts that sti!u"ate those e""s to!ake other !o"eu"es that at on neutro$hi"s, an !ake the! better at $hagoytiing etra

e""u"ar !irobes. n ( regu"atory e""s !ake ytokines (8 9, an that by aitiona" !eans

an inhibit %urther ( e"" ati'ation.

Slide #44: So ho& oes the !iro en'iron!ent regu"ate &hat ty$es o% e%%etor e""s e'e"o$)

(he !iro en'iron!ent oes that beause there are i%%erent ytokines in the !iro en'iron!ent

that he"$ eter!ine &hat the na'e ( e"" is going to i%%erentiation into. si!$"e &ay o% thinking

ho& that ou" &ork is that "ets say you are e$ose to a 'irus, an the 'irus has ertain


2/8

p%th&"en %''&ci%ted m&lecul%r p%ttern' ()*+),that engage &ith $attern reognition

ree$tors on innate i!!une e""s, an a onse6uene o% that signa"ing is that these e""s !ake

ytokines that &i"" $ro!ote the e'e"o$!ent o% (;1 ty$e e%%etor res$onse. So the $roution o%

IL12an +N 5 together &i"" "ea to the e'e"o$!ent o% a na'e ( e"" beo!ing a (;1 ty$e

e%%etor e"". (hen this (;1 e"" an !ake e'en !ore +N 5 an other ytokines that %eebak

on !aro$hages that !ake the! better at ki""ing that $athogen.


3/8

Slide #49: So the sa!e thing is true %or a"" the other e%%etor e"" subsets. So this is the sa!e

kin o% artoon %or (;2 e""s, an again you an see ( e"" ree$tors are essentia", but so are

ytokine ree$tors. So the +L-4 ree$tor engaging &ith +L-4 is an i!$ortant %ator o% the S((

$ath&ay that u$ regu"ates this !aster regu"atory transri$tion %ator that in the ase o% (;2 e""s

is a""e *T* 3. 8( 3 bins to other genes that regu"ate the $rogra!!ing o% e'e"o$!ent.

Slide #!0: So this is a nie su!!ary s"ie o% e'erything &e'e ta"ke about. So you shou"kno& these ytokines at the to$. n &hat these ytokines re%er to is the ytokines in the !iro

en'iron!ent that in%"uene the e'e"o$!ent o% these na'e e""s into these i%%erent ( e%%etor

e"" subsets. So %or ea!$"e, (8 9 is a ytokine thats in the !iro en'iron!ent, it ats on a

na'e *D4 ( e"" an $ro!ote e'e"o$!ent o% a ( regu"atory e"". +t oes this in $art by u$

regu"ating this transri$tion %ator a""e &)3. Lets o (;17 e""s, an here its a "itt"e %unny

beause you ha'e T a"so, but in on/untion &ith (8 9 you ha'e a"so +L-@. So &ith both,

instea o% beo!ing (reg e""s, the na'e *D4 ( e"" is !ore "ike"y to beo!e a (;17 e""

beause this o!bination o% ytokines $ro!otes the e$ression o% this transri$tion %ator a""e

T. +L-12 an +N 5 in the !iro en'iron!ent $ro!ote the e'e"o$!ent o% na'e ( e""s

that e$ress (-bet that is assoiate &ith (;1 e%%etor %untion. +L-4 is assoiate &ith (;2

e'e"o$!ent, an the e$ression o% 8( 3 is the transri$tion %ator, an these e""s !ake +Lan +L-4.

Slide #!1: So this is kin o% a su!!ary o% the &ay o% kin o% e$"aine it so %ar. Just rea"ie that

so!eti!es these e""s an s&ith their subset.

Slide #!2: ?e'e ta"ke about &hat regu"ates the e'e"o$!ent o% these i%%erent subsets, but

&e ha'ent ta"ke about &hat these subsets atua""y o. So &hat $atterns o% in%"a!!ations o

they inue)

Slide #!3: =ne o% the things (;1 e""s o is they !ake +N 5 &hih ati'ates !aro$hages,

&hih is a o!bination o% the (;1 e"" e$ressing *D40L that interats &ith *D40 on the

!aro$hage an !aking +N 5 &i"" $ro!ote !aro$hage ati'ation, an better enab"e the

!aro$hage to ki"" bateria. +t a"so he"$s *D e""s e'e"o$ ytotoi %untion. +n ontrast, (;2e""s !ake +L-4 &hih he"$s e""s unergo i!!unog"obu"in isoty$e s&ithing to !ake ertain

ty$es o% i!!unog"obu"in !o"eu"es suh as +g81 or +g that !eiate i%%erent ty$es o%

$athogen res$onses. =ne o% the things antiboy !o"eu"es are goo at is bining to $athogens

in the etra e""u"ar s$ae an %ai"itate their estrution.

Slide #!4: ?hat +! going to o no& is haraterie i%%erent ( e"" e%%etor subsets. ?hat kins

o% "y!$hokines they !ake. "y!$hokine is a ytokine that is !ae by a "y!$hoyte. ?hat "itt"e

a!ount o% he!okines they !ake, an a"so the ro"e o% iret e""-e"" ontat !eiate

!ehanis!s.

Slide #!!: (his is a tab"e that su!!aries the ytokines that the i%%erent e""s !ake. (here are

so!e that + &i"" ski$ beause they o not uni6ue"y e%ine a subset.

Slide #!-: (he %irst thing +"" ta"k about is (;1 e""s. (he ha""!ark ytokines these e""s !ake is

+N 5 an to a ertain etent, +L2, an a"so (N C. n the o!bination o% those ytokines

!ake the! 'ery goo at ati'ating !aro$hages, &hih !akes the! !ore $roin%"a!!atory. So

this is an ea!$"e o% &here the aa$ti'e i!!une res$onse is engaging an a!$"i%ying the

innate res$onse !eiate by in this ase a !aro$hage, &hih reruits a bunh o% other e""s.

(he other thing (;1 e%%etor e""s are assoiate &ith through +N 5 an +L2 is %ai"itate the


4/8

e'e"o$!ent an %untion o% *D ( e""s into cyt&t&ic T lymph&cyte'. So (;1 e""s are not

on"y assoiate &ith !aro$hage ati'ation, but a"so *D ytotoi ( e"" ati'ation. (his is

o%ten a""e cell medi%ted in5l%mm%ti&n.

Slide #!$: ;ere is a artoon o% (;1 e"", an it is he"$ing a !aro$hage. +t $roues +N 5 that

interats &ith +N 5 ree$tor on the !aro$hage. (he (;1 a"so e$resses CD40 li"%nd

(CD40L,&hih interats &ith the CD40on the !aro$hage, an that !akes it better ab"e to ki""the !irobes its interna"ie.

Slide #!8: =ne o% the things thats i!$ortant about this is that this a harateristi o% this

e%%etor ( e"" subset. (his is not so!ething na'e ( e""s o. Na'e ( e""s are ati'ate in the

"y!$h noe by enriti e""s. +t oes not ha'e this (;1 e%%etor subset. Just "ike ho& na'e

*D e""s o not ha'e ytotoi e%%etor %untion. ?hat that !eans is the %irst ti!e youre

sti!u"ate &ith so!ething, youre not ab"e to generate these e%%etor ty$e res$onses. ?hat you

o is sti!u"ate the e"" to go out an i%%erentiate into a e"" that is a$ab"e o% this %untion. +t

oesnt eert its %untion unti" it is resti!u"ate. So its at "east a t&o-ste$ thing. So you ha'e

$ri!ing o% the na'e ( e""s, an then you ha'e ree$osure to that e"". So i!agine you are

e$ose to an antigen that is in/ete into the subutaneous tissue. +ts $roesse by "oa"

antigen $resenting e""s. So as resu"t, these antigen $resenting e""s &i"" !ake ytokines that

&i"" reruit aitiona" e""s to the site. +% you'e a"reay got $ri!e (;1 e%%etor e""s, they &i"" be

reruite to that site an he"$ !aro$hages !eiate an e%%eti'e res$onse. (his is &hats

a""e a del%yed type hyper'en'iti6ity re'p&n'e. So a"" o% you in this roo! ha'e ha a AAD

test. So this is &hy AAD tests &ork. AAD tests are use to eter!ine i% you'e been $re'ious"y

e$ose to (. (he reason that !ost o% you in this roo! &ere AAD negati'e is beause you

ha'e not $ri!e na'e ( e""s that are s$ei%i %or AAD that ha'e e'e"o$e into a (;1 e%%etor

e"".


5/8

e%%etor e""s o!e into the !iro en'iron!ent an they try an he"$ the !aro$hages to ki"" the

bateria they $hagoytie. ut beause the bateria ha'e e'o"'e i!!une e'asion strategies

that !ake the abi"ity o% the !aro$hage to ki"" the bateria not so &e"", you ha'e this hroni

in%"a!!atory res$onse thats haraterie by "ots o% !aro$hage ati'ation thats not rea""y

&orking so &e"".

Slide #-2: So this is a su!!ary o% so!e o% the (;1 he"$er !ehanis!s in'o"'e in !eiatingthese ty$es o% in%"a!!atory res$onses. =ne thing &e ha'ent ta"ke about yet is the e$ression

o% this as "igan an &hen it engages &ith as it resu"ts in ki""ing o% the e"". ?e"" ta"k about

this !ore %or *D e""s, but (;1 e""s an o this too. (;1 uner so!e iru!stanes !ake +L-

2. +t an $ro!ote the e'e"o$!ent o% aitiona" e%%etor e""s. (hey !ake (N C &hih ats on

the "oa" enothe"iu! to !ake it stiky to reruit aitiona" e""s. (hey a"so !ake he!okines

&hih resu"ts in he!o attration o% aitiona" e""s.

7ue'ti&n Slide#-3:

ns&er:

* is &rong beause na'e *D4 ( e""s &i"" not !igrate to the site o% in%etion beause they nee

to %irst be $ri!e in the seonary "y!$hoi organ.

Slide #-4: So that &as (;1 e%%etor res$onses. =ne o% the ha""!ark ytokines %or (;2 e%%etor

res$onses is +L-4. So (;2 e""s &i"" !ake +L-4 an &i"" engage &ith +L-4 ree$tors on e""s an

&hen the e"" is a"so sti!u"ate by the e"" antigen ree$tor that &i"" in%"uene the abi"ity o%

these e""s to unergo &hats a""e i!!unog"obu"in isoty$e s&ithing. (his a""o&s e""s to

!ake +g. +g goes into the iru"ation an !ay bin to ree$tors on the sur%ae o% !ast e""s

an i% the +g !o"eu"es get ross-"inke by antigens that it sees, it &i"" ati'ate these m%'t

cell'to egranu"ate to re"ease hi't%minean other bioati'e !o"eu"es.

Slide #-!: Bast e""s ha'e granu"es o% hista!ine that ats on the "oa" tissue !iro en'iron!ent

to ause an a""ergi ty$e in%"a!!atory res$onse. =ther ytokines "ike +L are assoiate &ith

e&'in&phile'e"o$!ent in the bone !arro& an ati'ation in the $eri$hery. So it resu"ts in the

reruit!ent o% eosino$hi"s to these in%"a!!atory sites. nother thing that ha$$ens is a ytokine

a""e +L13 ats on "oa" e$ithe"ia" e""s es$eia""y in the gut an "ung, it &i"" $ro!ote the

$roution o% !uus, &hih he"$s get ri o% "arge !u"tie""u"ar organis!s "ike &or!s.

Slide #--: (;2 in%"a!!atory res$onses are o%ten assoiate &ith a""ergy. 'ery o!!on

a""ergi %or! o% in%"a!!ation is asth!a. (his is a"" initiate by (;2 ty$e e%%etor res$onse an

this is /ust a artoon &here you ha'e (;2 e""s !aking +L-4, &hih in turn ats on e""s, &hih

$ro!otes +g $roution, &hih %ai"itates !ast e"" egranu"ation, &hih &i"" $ro!ote an aute,

a""ergi reation. "so (;2 e""s !ake +L, &hih $ro!otes eosino$hi" reruit!ent i!$ortant in

the asth!a in%"a!!atory res$onse. n so!eti!es i% it is hroni, &ith hroni ytokine

$roution an in%"a!!ation, you &i"" a"so get tissue re!oe"ing an a"teration o% the $hysio"ogyo% the air&ay !aking it hronia""y i%%iu"t %or these %o"ks to breathe.

Slide #-$: (h17 e""s are e'e"o$e by (8 9 an +L-@ ytokines. (hey are haraterie by

their abi"ity to $roue +L-17 that at on e""s in the !iro en'iron!ent "ike enothe"ia" e""s an

stro!a" e""s to re"ease ytokines that in turn at on neutro$hi"s. Neutro$hi"s are rea""y goo

$hagoyti e""s, an their res$onse is assoiate &ith the "earane o% etra e""u"ar

$athogens. (;17 is a"so assoiate &ith ati'ation o% a 'ariety o% autoi!!une iseases

in"uing !u"ti$"e s"erosis, *rohns isease. (his is thought to be ause by a ysregu"ation o%


6/8

(;17 e%%etor res$onses. So the iea is i% you an target s$ei%i ytokines that regu"ate the

e'e"o$!ent anor %untion o% (;17 e""s, &hih &ou" be a thera$euti a$$roah to ea" &ith

so!e o% these autoi!!une iseases.

Slide #-8: e"ul%t&ry T cell'are another set o% e%%etor e""s that instea o% $ro!oting an

i!!une res$onse an $roteting us against !irobes, it inues the e'e"o$!ent o% regu"atory

%untion so that &e an turn o% i!!une res$onses so &e are at "ess risk o% e'e"o$ingautoi!!une iseases. +n orer %or a na'e ( e"" to e'e"o$ into a regu"atory ( e"", its

i!$ortant that (8 9 is in the !iro en'iron!ent, an its assoiate &ith a transri$tion %ator

a""e oA3.

Slide #-9: +% you ha'e a na'e *D ( e"" that gets $ri!e, it !ay e'e"o$ into a ytotoi ( e""

i% it gets the a$$ro$riate signa"s "ike ( e"" ree$tor signa"s, osti!u"atory signa"s, an ytokine

signa"s +L2 an +N 5 $erha$s !ae by another *D4 e"". n that &i"" a""o& the e"" to e'e"o$

ytotoi e%%etor %untion an ki"" the e"" e$ressing B;* $e$tie "igan a%ter its e'e"o$e

this %untion.

Slide #$0: >e!e!ber this is a $roess that takes se'era" ays, an it re"ies on these e""s

transribing genes that ha'e this ytotoi e%%etor %untion.

Slide #$1: So this is ho& that &orks. So i% you e'e"o$ the ytotoi e%%etor %untion in the

$eri$hery an you i!agine these are in%"uena in%ete bronhio"e e$ithe"ia" e""s the *D e""s

are "ooking %or these in%"uena $e$ties $resente by the B;* "ass 1 !o"eu"es. +% the *D

e"" is $ri!e an e$resses ( e"" ree$tors %or that $e$tie, it &i"" engage, get sti!u"ate, an

re"ease s$ei%i ytokines an other !o"eu"es that &i"" ki"" the in%ete e"" but s$are

neighboring hea"thy e""s. (he ki""ing is targete to&ars the antigen $resenting e"".

Slide #$2: (he &ay this &orks is &hen the ytotoi ( e"" is engaging &ith the target e"" thats

e$ressing B;* "ass 1 $e$tie "igan, it has granu"es or "ysoso!es in the ytoso" that are

trans$orte to the immun&l&"ic%l 'yn%p'ean inter%ere &ith the !e!brane struture o% the

target e"". So you ha'e t&o !o"eu"es that are ritia" %or this. =ne !o"eu"e is per5&rinanthats the !o"eu"e that %or!s the &ho"e in the !e!brane o% the target e"". (his a""o&s this

other !o"eu"e to get in the target e"" a""e "r%nyme, &hih are serine $roteases that

ati'ate as$ases that ati'ate $rogra!!e e"" eath. So this is $robab"y the !ain &ay

ytotoi ( e""s ki"" target e""s. nother &ay this !ay &ork is the ytotoi ( e"" !ay e$ress

*S li"%nd (*SL,that &hen it engages &ith *Son the target e"", that !ay a"so inue e""

eath o% the target e"". (he S ree$tor a"so ati'ates as$ases &hih inue e"" eath.

Slide #$3: So this is a artoon o% this $roess. So one o% the ha""!arks o% a e"" thats e'e"o$e

ytotoi e%%etor %untion is that it has transribe genes that enoe %or the grany!e an

$er%orin $roteins. So na'e *D ( e""s o not e$ress grany!e or $er%orin. So i% the ytotoi

( e""s ( e"" ree$tors get engage &ith B;* "ass 1 $e$tie o!$"ees, it !akes these

granu"es get serete right &here the target e"" is. So this is &hat this "ooks "ike using%"uoresent "abe""ing. ?hats in green here is "abe""ing o% the !irotubu"e o!$"e an thats

i!$ortant %or arraying these granu"es an trans$orting to&ars the inter%ae &here the target

e"" is. So be%ore this ( e"" is triggere, the granu"es are is$erse throughout the e"", but here

&hen the e"" is $hysia""y interating &ith the target e"", you an see the !irotubu"e o!$"e

a"" $ointing to&ars the target e"", an the granu"es are a"" trans$orte to the inter%ae.


7/8

Slide #$4: So this is /ust a artoon o% that $roess. (his is an e"etron !irogra$h &ith the (

e""s granu"e ontents being etrue to&ars the target e"". So thats the !a/or &ay by &hih

ytotoi ( "y!$hoytes ki"" other e""s.

Slide #$!: So this is the other &ay that + !entione. *ytotoi ( e""s an so!eti!es (;1 e""s

e$ress asL that engages &ith as, &hih is a !e!ber o% the (N ree$tor su$er%a!i"y. (he

&ay these ree$tors &ork is they assoiate &ith $reursor c%'p%'e!o"eu"es, or $roas$ases,ati'ates those $roas$ases &hih initiates e"" eath.

7ue'ti&n Slide#$-:

ns&er: an D

is &rong. is $artia""y orret beause *D4 e""s are "ike"y to beo!e ( he"$er e""s &hi"e

*D e""s are "ike"y to beo!e ytotoi e""s. * is triky. +t is &rong beause +L-12 is neee to

e'e"o$ (h1 e""s, but (h1 e""s the!se"'es o not serete +L-12, it is serete by antigen

$resenting e""s. D is orret. is inorret beause e""-!eiate res$onse is $ro!ote by (h1

e""s. is &rong beause S((@ ati'ation is assoiate &ith (h2 e'e"o$!ent.

Slide #$$: So "ets ta"k about the ty$ia" ourse o% ( e"" ati'ation. So &e see here that B;*$e$tie o!$"ees are $resente by antigen $resenting e""s. (hat inues "ona" e$ansion.


8/8

sa& tetanus, an there%ore the aa$ti'e i!!une res$onse &as not e%%eti'e enough to ontro"

an eraiate the in%etion.

13 14 immunology leitenberg tcellimmunity 01-27-14

Documents