T-cell co-stimulation by CD28-CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development.
OBJECTIVE
T-cells are central to the immune response responsible for native atherosclerosis. The objective of this study is to investigate T-cell contribution to post-interventional accelerated atherosclerosis development, as well as the role of the CD28-CD80/86 co-stimulatory and Cytotoxic T-Lymphocyte Antigen (CTLA)-4 co-inhibitory pathways controlling T-cell activation status in this process.


RESULTS
The role of T-cells and the CD28-CD80/86 co-stimulatory and CTLA-4 co-inhibitory pathways were investigated in a femoral artery cuff mouse model for post-interventional remodeling, with notable intravascular CTLA-4+ T-cell infiltration. Reduced intimal lesions developed in CD4(-/-) and CD80(-/-)CD86(-/-) mice compared to normal C57Bl/6J controls. Systemic abatacept-treatment, a soluble CTLA-4Ig fusion protein that prevents CD28-CD80/86 co-stimulatory T-cell activation, prevented intimal thickening by 58.5% (p=0.029). Next, hypercholesterolemic ApoE3*Leiden mice received abatacept-treatment which reduced accelerated atherosclerosis development by 78.1% (p=0.040) and prevented CD4 T-cell activation, indicated by reduced splenic fractions of activated KLRG1+, PD1+, CD69+ and CTLA-4+ T-cells. This correlated with reduced plasma interferon-γ and elevated interleukin-10 levels. The role of CTLA-4 was confirmed using CTLA-4 blocking antibodies, which strongly increased vascular lesion size by 66.7% (p=0.008), compared to isotype-treated controls.


CONCLUSIONS
T-cell CD28-CD80/86 co-stimulation is vital for post-interventional accelerated atherosclerosis development and is regulated by CTLA-4 co-inhibition, indicating promising clinical potential for prevention of post-interventional remodeling by abatacept.
Dept. of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Dept. of Surgery, LUMC, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
M M
MM
Ewing
J C
JC
Karper
S
S
Abdul
R C M
RC
de Jong
H A B
HA
Peters
M R
MR
de Vries
A
A
Redeker
J
J
Kuiper
R E M
RE
Toes
R
R
Arens
J W
JW
Jukema
P H A
PH
Quax
D000069594:Abatacept; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051940:B7-2 Antigen / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005263:Femoral Artery / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D007111:Immunity, Cellular; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept
Atherosclerosis; CTLA-4; Co-stimulation; Inflammation; T-cells