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Regulation of T cell Immunity

3103 Nov 2023

Mark Larché
Divisions of Clinical Immunology & Allergy and Respirology,
Dept. Medicine & Firestone Institute for Respiratory Health,
McMaster University,
Hamilton, ON
Canada
 Homeostasis

effector regulator

regulator effector

Tolerance Inflammation
Risk assessment: Cancer Tissue damage, Autoimmunity
Balance between pro- and anti-inflammatory subsets
determines immune response
Health
Th2

“Defective regulation”
- Cause or consequence?

Autoimmunity Allergy

Th2 Th2
Mechanisms of regulation of T cell responses
* Ignorance
- Testes, anterior chamber of the eye

» Clonal deletion
- Central tolerance in the thymus

* Anergy
- TeR stimulation without costimulation, exhaustion

* Sequestration
- Down-regulation of homing receptors, competition for ligands

» Active regulation
- Action of regulatory T cells
lgnorance
Just not enough material to work with......

....iIf peptide-MHC complexes are too few, the high

activation threshold requirements for naive T cells
cannot be met

-
g)
5 Sisyphus
I8 Y
Lesley Drysdale
Clonal deletion
Central tolerance in the thymus deletes most
potentially autoreactive T cells......

....those that escape can be deleted in the

periphery through the induction of apoptosis
 moderate Here also,
binding

“lgnorance is death”
(knowledge is life)
Swami Vivekananda

dendritic
cell

tight
binding
Figure 7.18 The Immune System, 4th ed. (© Garland Science 2015)
Multiple distinct pathways contribute to regulation

M By or even death!

Signal 1 alone (in priming) can also activate Bim

leading to activation of apoptosis pathways........

....... the lack of CD28 costimulation means anti-

apoptotic Bcl-2 and Bcl-X, are not induced

double whammy
 Regulation of clonal expansion

Number of antigen-specific CD8 + T cells

70 —90% of CD8+ T cells die by apoptosis
during contraction
Expansion Contraction
Phase B Phase B Persistence beyond contraction phase
i i depends upon many factors

0 7-14 20-30 Lifetime

Day following immunization

Some get exhausted and express

Pink cell is triggered by inhibitory receptors,
antigen Some kill each other......
Anergy
Paralysis or “hyporesponsiveness”, but not

....some evidence that anergy can be recovered

from (for example by vacuuming up IL-2)
 Full or partial signalling contributes to functional outcome

Naive
T cell 80 T

c o -anti-CD28
o _ R
TD = +anti-CD28
OS]
S x o SC-Kd/CW3
o £
= Q
R
o O J
|_
O

0 _7/.001 .O 0.1 1 10 100

Non-professional APC Immobilized SC-Kd/HA

(ng/ml)
—_— I O MemoryT cell responses potentiated by costimulation

Quantity/frequency/quality of recognition can also influence outcome

Pardigon N, et al. Role of co-stimulation in CD8+ T cell activation. Int Immunol. 1998 May;10(5):619-30
 Naive T cells

E1E2,68

co-
stimulator

T-cell
receptor

Inactivation (anergy) or deletion of T cell

No effect on T cell Decreased TCR signaling through/mdyction
of GRAIL and activation of Cbl
Figure 9.23 Janeway’s Immunobiology, 8ed. (© Garland Science 2012)

GRAIL and Cbl-b are ubiquitin ligases; when the TcR signals in naive cells
without costimulation, components of the TcR are targeted for degradation
reducing T cell receptor density on the cell surface
 ...... but it also competes for
all the B7 molecules on the
APC, sequestering them from
CD28
antigen-presenting cell

N ..... this is an important

mechanism of suppression
employed by T, which
MHC express high levels of CTLA-4
B7.1 class Il
@
Blocking CTLA-4 is a target
cD4 for checkpoint inhibition
therapy in cancer

1)
’ v activated T cell
b
Figure 9.22 Janeway’s Inmunobiology, 8ed. (© Garland Science 2012)
Jim Allison
 Dan Moldaver & Chris Rudulier
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) o n
Immunotherapy = 3000004 Tet+ CD4+ ~81
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Recived: 11 September 2015 | Reised: 15 Fbruary2019 | Acceped: 1 Morch 2019
Dor o1l s667
(o3 IL-5+ T-cells D IL-13+ T-cells
ORIGINAL ARTICLE Allergy 2 WILEY
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Experimental Allergy and Immunology o o
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Modulation of CRTh2 expression on allergen-specific T cells < = P
o3 ° o3 o 10
following peptide immunotherapy T & 54 T s
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Christopher
D. Rudulier' | Elena Tonti' | Eddie James® | WilliamW. Kwok?© | C) o
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Mark Larché!3®
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N M N A M N AN
Active regulation
Healthy balance maintained by regulatory T cells
and IL-10

Allergic Healthy

>
g 10 P
* Balance of Th1/Th2/Tr Eos &
% | ——= %

* Healthy individuals have 8 25{ O 2 A

predominant IL-10 responses g 0 i @ %
IL-4 IFN-y IL-10 IL-4 IFN-y IL-10
to aero- and food allergens ODerp1 ABetvi @Pyrc5 MCoraf
B Allergic Healthy

Allergic individuals are 101° » ——"

frequency / 104 T cells

deficient in Tr 75 **—+qflfi

[9)]

O
25%
. e E’A
DA

IL-4 IFN-y ILl—10 IL-4 IFN-y IL-10

Akdis M et al. J. Exp. Med 2004 ODerp1 ABetv1
 Signal 3 for regulation

dendritic
cell

iLs, TeF-p
MHC high TGF-8 high TGF-B Th17
class Il lowIL-6, IL-23 high IL-6, IL-23
naive naive 41 \ Th? @
CD4
Teell
CD4 @ 1L-17
Tcell - Autoimm dis
TCR U (62
‘Autoimmune disease
Mla‘:obluulf:m'.fn?e
Anti-tumor immunity IL-4, 5,10, 13
Parasite infection
ALY

Sakaguchi et al. Cell 133; 775-787 2008

FOXP3* Treq

Q.
[ ] e
&inhibit J

Tal T2
Figure 11.4 Janeway’s Immunobiology, 8ed. (© Garland Science 2012)

Figure 9.19 Janeway’s Inmunobiology, 8ed. (© Garland Science 2012)

Regulatory T cells: Where do they come Treg cells

from?
Development in the thymus inhibit

T cells that bind self epitopes with high affinity but do

not undergo negative selection will become natural
immature
Tregs (nTregs) dendritic cell

Development in the periphery

T cells that are triggered by self-antigen, food antigen or
microbial antigen following exposure to tolerogenic DCs
become inducible Tregs (iTreg)
lack of
T-cell activation
 Natural and adaptive regulatory T cells (T,.)
Natural/thymus-derived Adaptive/induced

TGFB/ all-trans retinoic acid/rapamycin

Th3

Tr1

IL-10
Cell contact-dependent inhibition Cytokine-dependent Vitamin D3/dexamethazone

CD4* CD25* Activated Tegr CD4/8* CD25*-

CD25" !
CD25bright Treg Foxp3neg/ros
Foxp3*
CD127" -
“anergic” CTLA-4, GITR, neuropilin A, PD-1, LAG-3
demethylated Foxp3 (TSDR)
 g Shut down effector T cells in a variety of ways

a Inhibitory cytokines b Cytolysis

Membrane- Granzyme A orgranzyme B

tethered TGFB T GFB

° °
—|
°
[ Perforln pore
Treg cell IL- 35 IL-10 Effector T cell Apoptotic effector
Tcell

d Targeting dendritic cells

Death due
to cytokine
deprivation

Adenosine

Inhibition of DC maturation
and function

D. Vignali Nat Rev Immunol. 2008 Jul;8(7):523-32

 Apoptosis

Tryptophan
| Lot s CXCL1
/ /
, D0 |exerz
SOCs3
Perforin Granzyme HO-1
Kyurenine g \
[ \ ®e .
Y \epae L Proliferation
)
olL-35 NKG20
® @ TGF-B
IL-10 CTLA-4 \
CD39/ CD73\ S ' . IL- M1 !I'Lr]iu
\ o 7/ /\ acrophagg IL-18
e
ATP

T ) oPD-1 3 ICOS
Monocyte ®
Adenosine acrophag (X
AMP IL-5 IL-10
IL-13 cp163t” Spzoet

Romano M Frontiers in Immunology 2019

Nature’s Experiment # 1:
Children outgrowing milk “allergy” have more T4,

Allergen-responsive CD4"CD25* Regulatory T Cells o P . .

in Children who Have Outgrown Cow’s Milk Allergy 80% of cow’s milk allergic children
_ _ outgrow their allergy
Malin R. Karlsson,! Jarle Rugtveit,'-? and Per Brandtzaeg'

*Laboratory for lmmunohistochemistry and Inmunopathology (LIIPAT), Institute of Pathology,

Rikshospitalet University Hospital, N-0027 Oslo, Norway 60 - P=0.0006
2Department of Paediatrics, Ulleval University Hospital, NO-0407 Oslo, Nonway o
P=0.0003
. 50 - o
g 2 @ Allergic patients
o O Tolerant children
Some are clinically tolerant to milk challenge, others ;g 40 - o
remain intolerant ) 8
2 2 301 &
. . . =g e o
Tolerance is accompanied by a higher frequency of é H o 8
CD4*CD25* T cells gfi 201
2
10
These cells mediated active suppression (in the lab) ® O So
ik I
Before in vivo After in vivo
challenge challenge

??
But....cause or effect?: Karlsson, Rugtveit & Brandzaeg. J Exp Med 2004
Nature’s Experiment # 2:
IL-10-mediated immune tolerance in bee keepers

bee stings / month >

response (cm)
skin late phase
O=_2NWhO
-
O

/
skin late phase
response
OO
B
N
o
[®H]thymidine incorporation (O
(cpm x 1000)
o

Meiler et al., J Exp Med 2008 Question: who is this brilliant scientist?
Nature’s Experiment # 3:
Viruses exploit the immunoregulatory functions of IL-10
6 6

(mean ng/ml +/-SD)

7-IFN secretion
« EBV and CMV make viral IL-10
homologues
« EBV seropositive individuals

deo
make IL-10 responses to LMP1

(mean cpm x 1073 +/-SD)

Proliferation
Latent Membrane Protein

&
]
Marshall, Vickers & Barker. J Immunol 2003 0
ST T -
Stimulus | ConA | PPD | KLH ConA | PPD | KLH

EBV status EBV seropositive EBV scroncgative

Xuekui Yu et al PNAS 2005

 Regulatory T cells as therapy for ........just about anything

kil B8
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 Exploiting co-inhibitory receptors for therapy

PD-L1 binds to PD-1 and inhibits Blocking PD-L1 or PD-1 allows

T cell killing of tumor cell T cell killing of tumor cell PD-1 signalling
activates phosphatases
that reduce signalling
Tumor cell Tumor cell
death
Exhausted T cells have
lots of PD-1 due to
chronic exposure to
antigen

Preventing PD-1 from

engaging its ligands
(PD-L1 and PD-L2) can
allow full signalling
activity and T cell
function

Tasuko Checkpoint inhibitors take the brake off

Honjo

NIH National Cancer Institute https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=772606

It’s all about balance

Darcy Bussell, Royal Ballet

Any questions?

[email protected]