Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

Maria M. Xu, Antoine Ménoret, Sarah Anne E. Nicholas, Sebastian Günther, Eric J. Sundberg, Beiyan Zhou, Annabelle Rodriguez-Oquendo, Patrick A. Murphy, Anthony T. Vella

Research output: Contribution to journalArticle

Abstract

Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4-1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity.

Original languageEnglish (US)
Pages (from-to)H1480-H1494
JournalAmerican journal of physiology. Heart and circulatory physiology
Volume316
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

T-Lymphocytes
Tunica Intima
Antigens
CD137 Antigens
Atherosclerosis
Adoptive Transfer
Virus Diseases
Atherosclerotic Plaques
Autoimmunity
Inbred C57BL Mouse
Innate Immunity
Digestion
Flow Cytometry
Animal Models
Morbidity

Keywords

  • atherosclerosis
  • CD137
  • CD8 T cell
  • inflammation
  • interferon-γ

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci. / Xu, Maria M.; Ménoret, Antoine; Nicholas, Sarah Anne E.; Günther, Sebastian; Sundberg, Eric J.; Zhou, Beiyan; Rodriguez-Oquendo, Annabelle; Murphy, Patrick A.; Vella, Anthony T.

In: American journal of physiology. Heart and circulatory physiology, Vol. 316, No. 6, 01.06.2019, p. H1480-H1494.

Research output: Contribution to journalArticle

Xu, Maria M. ; Ménoret, Antoine ; Nicholas, Sarah Anne E. ; Günther, Sebastian ; Sundberg, Eric J. ; Zhou, Beiyan ; Rodriguez-Oquendo, Annabelle ; Murphy, Patrick A. ; Vella, Anthony T. / Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci. In: American journal of physiology. Heart and circulatory physiology. 2019 ; Vol. 316, No. 6. pp. H1480-H1494.
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