Abstract
CD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8+ cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4+ or CD8+ T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8+ T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4−/−, CD28−/− knockout and CTLA4Ig treated WT recipients, but not in WT or CD8−/− knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8+ T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8+ alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection.
Highlights
Full T cell activation in response to alloantigen presentation requires, in addition to stimulation through the TCR, a costimulatory signal [1]
Using a novel fusion protein CD160Ig we demonstrate that blocking the CD160:CD160L interaction prolongs fully mismatched heart transplant survival in a model of CD28-independent CD8+ mediated allograft rejection by inhibiting alloreactive CD8+ T cell proliferation, effector/memory expansion and cytokine generation
We found that expression of CD160 was significantly upregulated on both CD4+CD44highCD62Llow (9.560.3%) and to a higher degree CD8+CD44highCD62Llow effector/memory T cells (14.561.5%), suggesting that CD160 expression is induced after CD8+ T cell activation
Summary
Full T cell activation in response to alloantigen presentation requires, in addition to stimulation through the TCR, a costimulatory signal [1]. While CD28 blockade has been shown to prolong allograft survival in some transplant models [2,3,4,5,6], less success has been observed in more stringent models [7] This process is thought to be mediated predominantly by NK cells [8,9], CD8+ T cells [10,11,12,13] and effector/memory responses [14], which appear to be less dependent on CD28 costimulation, and might utilize alternative costimulatory pathways for activation [15]. Using a novel fusion protein CD160Ig we demonstrate that blocking the CD160:CD160L interaction prolongs fully mismatched heart transplant survival in a model of CD28-independent CD8+ mediated allograft rejection by inhibiting alloreactive CD8+ T cell proliferation, effector/memory expansion and cytokine generation
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