https://orcid.org/0000-0002-0696-7197
Key Points
oIL-2Rβ Tregs can be selectively expanded in vivo with oIL-2 administered after allo-HSCT.
Smaller numbers of oIL-2Rβ Tregs–oIL-2 are needed to reduce clinical scores, improve GVHD survival, and maintain GVT responses.
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex–disparate GVHD model of lethally irradiated BALB/c mice given T cell–depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ–transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.
References
1.
Blazar
BR
, Hill
GR
, Murphy
WJ
. Dissecting the biology of allogeneic HSCT to enhance the GvT effect whilst minimizing GvHD
. Nat Rev Clin Oncol
. 2020
;17
(8
):475
-492
.2.
Wingard
JR
, Majhail
NS
, Brazauskas
R
, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation
. J Clin Oncol
. 2011
;29
(16
):2230
-2239
.3.
Zeiser
R
, Blazar
BR
. Acute graft-versus-host disease - biologic process, prevention, and therapy
. N Engl J Med
. 2017
;377
(22
):2167
-2179
.4.
Hill
L
, Alousi
A
, Kebriaei
P
, Mehta
R
, Rezvani
K
, Shpall
E
. New and emerging therapies for acute and chronic graft versus host disease
. Ther Adv Hematol
. 2018
;9
(1
):21
-46
.5.
Lucca
LE
, Dominguez-Villar
M
. Modulation of regulatory T cell function and stability by co-inhibitory receptors
. Nat Rev Immunol
. 2020
;20
(11
):680
-693
.6.
Taylor
PA
, Lees
CJ
, Blazar
BR
. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality
. Blood
. 2002
;99
(10
):3493
-3499
.7.
Brunstein
CG
, Miller
JS
, Cao
Q
, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics
. Blood
. 2011
;117
(3
):1061
-1070
.8.
Brunstein
CG
, Miller
JS
, McKenna
DH
, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect
. Blood
. 2016
;127
(8
):1044
-1051
.9.
Pierini
A
, Strober
W
, Moffett
C
, et al. TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment
. Blood
. 2016
;128
(6
):866
-871
.10.
Meyer
EH
, Laport
G
, Xie
BJ
, et al. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients
. JCI Insight
. 2019
;4
(10
):e127244
.11.
Edinger
M
, Hoffmann
P
, Ermann
J
, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation
. Nat Med
. 2003
;9
(9
):1144
-1150
.12.
Trenado
A
, Charlotte
F
, Fisson
S
, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia
. J Clin Invest
. 2003
;112
(11
):1688
-1696
.13.
Raffin
C
, Vo
LT
, Bluestone
JA
. T(reg) cell-based therapies: challenges and perspectives
. Nat Rev Immunol
. 2020
;20
(3
):158
-172
.14.
Koreth
J
, Matsuoka
K
, Kim
HT
, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease
. N Engl J Med
. 2011
;365
(22
):2055
-2066
.15.
Saadoun
D
, Rosenzwajg
M
, Joly
F
, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis
. N Engl J Med
. 2011
;365
(22
):2067
-2077
.16.
He
J
, Zhang
X
, Wei
Y
, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus
. Nat Med
. 2016
;22
(9
):991
-993
.17.
Hirakawa
M
, Matos
TR
, Liu
H
, et al. Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells
. JCI Insight
. 2016
;1
(18
):e89278
.18.
Spangler
JB
, Tomala
J
, Luca
VC
, et al. Antibodies to interleukin-2 elicit selective T cell subset potentiation through distinct conformational mechanisms
. Immunity
. 2015
;42
(5
):815
-825
.19.
Trotta
E
, Bessette
PH
, Silveria
SL
, et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism
. Nat Med
. 2018
;24
(7
):1005
-1014
.20.
McDonald-Hyman
C
, Flynn
R
, Panoskaltsis-Mortari
A
, et al. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner
. Blood
. 2016
;128
(7
):1013
-1017
.21.
Sockolosky
JT
, Trotta
E
, Parisi
G
, et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes
. Science
. 2018
;359
(6379
):1037
-1042
.22.
Zhang
Q
, Hresko
ME
, Picton
LK
, et al. A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia
. Sci Transl Med
. 2021
;13
(625
):eabg6986
.23.
Aspuria
PJ
, Vivona
S
, Bauer
M
, et al. An orthogonal IL-2 and IL-2Rβ system drives persistence and activation of CAR T cells and clearance of bulky lymphoma
. Sci Transl Med
. 2021
;13
(625
):eabg7565
.24.
Hirai
T
, Ramos
TL
, Lin
PY
, et al. Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance
. J Clin Invest
. 2021
;131
(8
):e139991
.25.
Saha
A
, O'Connor
RS
, Thangavelu
G
, et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
. J Clin Invest
. 2016
;126
(7
):2642
-2660
.26.
Blazar
BR
, Taylor
PA
, McElmurry
R
, et al. Engraftment of severe combined immune deficient mice receiving allogeneic bone marrow via in utero or postnatal transfer
. Blood
. 1998
;92
(10
):3949
-3959
.27.
Lohmeyer
JK
, Hirai
T
, Turkoz
M
, et al. Analysis of T cell repertoire and transcriptome identifies mechanisms of regulatory T cell (Treg) suppression of GvHD. Published online 27 December 2022. Blood
. http://doi.org/10.1182/blood.2022017982.28.
Nguyen
VH
, Zeiser
R
, daSilva
DL
, et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation
. Blood
. 2006
;109
(6
):2649
-2656
.29.
Ding
Y
, Xu
J
, Bromberg
JS
. Regulatory T cell migration during an immune response
. Trends Immunol
. 2012
;33
(4
):174
-180
.30.
Wysocki
CA
, Jiang
Q
, Panoskaltsis-Mortari
A
, et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease
. Blood
. 2005
;106
(9
):3300
-3307
.31.
Taylor
PA
, Panoskaltsis-Mortari
A
, Swedin
JM
, et al. L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection
. Blood
. 2004
;104
(12
):3804
-3812
.32.
Ermann
J
, Hoffmann
P
, Edinger
M
, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD
. Blood
. 2005
;105
(5
):2220
-2226
.33.
Hirai
T
, Lin
PY
, Simonetta
F
, et al. Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD
. Blood Adv
. 2021
;5
(11
):2528
-2538
.34.
Hefazi
M
, Bolivar-Wagers
S
, Blazar
BR
. Regulatory T cell therapy of graft-versus-host disease: advances and challenges
. Int J Mol Sci
. 2021
;22
(18
):9676
.35.
Romano
M
, Tung
SL
, Smyth
LA
, Lombardi
G
. Treg therapy in transplantation: a general overview
. Transpl Int
. 2017
;30
(8
):745
-753
.36.
Peterson
LB
, Bell
CJM
, Howlett
SK
, et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease
. J Autoimmun
. 2018
;95
:1
-14
.37.
Lee
SY
, Cho
ML
, Oh
HJ
, et al. Interleukin-2/anti-interleukin-2 monoclonal antibody immune complex suppresses collagen-induced arthritis in mice by fortifying interleukin-2/STAT5 signalling pathways
. Immunology
. 2012
;137
(4
):305
-316
.38.
Pérol
L
, Martin
GH
, Maury
S
, Cohen
JL
, Piaggio
E
. Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease
. Immunol Lett
. 2014
;162
(2 pt B
):173
-184
.39.
Bacchetta
R
, Passerini
L
, Gambineri
E
, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations
. J Clin Invest
. 2006
;116
(6
):1713
-1722
.40.
Radstake
TR
, van Bon
L
, Broen
J
, et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFbeta expression
. PLoS One
. 2009
;4
(6
):e5981
.41.
Barron
L
, Dooms
H
, Hoyer
KK
, et al. Cutting edge: mechanisms of IL-2–dependent maintenance of functional regulatory T cells
. J Immunol
. 2010
;185
(11
):6426
-6430
.42.
Abbas
AK
, Trotta
E
, Simeonov
DR
, Marson
A
, Bluestone
JA
. Revisiting IL-2: biology and therapeutic prospects
. Sci Immunol
. 2018
;3
(25
):eaat1482
.43.
Gocher
AM
, Handu
S
, Workman
CJ
, Vignali
DAA
. Interferon gamma production by regulatory T cells is required for response to cancer immunotherapy
. J Immunol
. 2020
;204
(suppl 1
). 244.248-244.248.44.
Furlan
SN
, Singh
K
, Lopez
C
, et al. IL-2 enhances ex vivo-expanded regulatory T-cell persistence after adoptive transfer
. Blood Adv
. 2020
;4
(8
):1594
-1605
.45.
Krenger
W
, Hill
GR
, Ferrara
JL
. Cytokine cascades in acute graft-versus-host disease
. Transplantation
. 1997
;64
(4
):553
-558
.46.
Xiao
Z
, Alam
IS
, Simonetta
F
, et al. ICOS immunoPET enables visualization of activated T cells and early diagnosis of murine acute gastrointestinal GvHD
. Blood Adv
. 2022
;6
(16
):4782
-4792
.47.
Taylor
PA
, Panoskaltsis-Mortari
A
, Freeman
GJ
, et al. Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM)
. Blood
. 2005
;105
(8
):3372
-3380
.48.
Riegel
C
, Boeld
TJ
, Doser
K
, Huber
E
, Hoffmann
P
, Edinger
M
. Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells
. Leukemia
. 2020
;34
(3
):895
-908
.49.
Heinrichs
J
, Li
J
, Nguyen
H
, et al. CD8(+) Tregs promote GVHD prevention and overcome the impaired GVL effect mediated by CD4(+) Tregs in mice
. Oncoimmunology
. 2016
;5
(6
):e1146842
.50.
Jiang
H
, Fu
D
, Bidgoli
A
, Paczesny
S
. T cell subsets in graft versus host disease and graft versus tumor
. Front Immunol
. 2021
;12
(2
):761448
.51.
Negrin
RS
. Immune regulation in hematopoietic cell transplantation
. Bone Marrow Transplant
. 2019
;54
(2
):765
-768
.52.
Pierini
A
, Colonna
L
, Alvarez
M
, et al. Donor requirements for regulatory T cell suppression of murine graft-versus-host disease
. J Immunol
. 2015
;195
(1
):347
-355
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