Journal
BLOOD
Volume 112, Issue 4, Pages 1259-1268Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-12-130773
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Funding
- NCI NIH HHS [P30 CA023108, R01 CA124515, R01CA124515] Funding Source: Medline
- NCRR NIH HHS [P20 RR016437, 2P20RR016437-06] Funding Source: Medline
- NIAID NIH HHS [R01 AI051547, P01 AI051877, AI5154, AI51877] Funding Source: Medline
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Robust T-cell responses without autoimmunity are only possible through a fine ballance between activating and inhibitory signals. We have identified a novel modulator of T-cell expansion named proliferation-induced lymphocyte-associated receptor (PILAR). Surface PILAR is markedly upregulated on CD4 and, to a lesser extent, on CD8 T cells on T-cell receptor engagement. In absence of CD28 costimulation, PILAR signaling through CD161 supports CD3 antibody-dependent and antigen-specific T-cell proliferation by increasing the expression of antiapoptotic Bcl-xL and induces secretion of T helper type 1 cytokines. These effects are abrogated by PILAR blockade with specific antibodies, which decrease surface levels of CD28. In contrast, PILAR induces apoptotic death on naive and early activated T cells if CD161 engagement is blocked. PILAR is expressed by approximately 7% to 10% of CD4 T-cells in 2 samples of inflammatory synovial fluid, suggesting a potential role in the pathogenesis of joint inflammation. In addition, in the ovarian cancer microenvironment, effector T cells express PILAR, but not CD161, although expression of both can be augmented ex vivo. Our results indicate that PILAR plays a central role in modulating the extent of T-cell expansion. Manipulation of PILAR signaling may be important for treatment of autoimmune diseases and cancer.
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