PILAR is a novel modulator of human T-cell expansion.
Robust T-cell responses without autoimmunity are only possible through a fine balance 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 up-regulated 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-specificT-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.
Department ofMicrobiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA.
Eduardo
E
Huarte
Juan R
JR
Cubillos-Ruiz
Yolanda C
YC
Nesbeth
Uciane K
UK
Scarlett
Diana G
DG
Martinez
Xavier A
XA
Engle
William F
WF
Rigby
Patricia A
PA
Pioli
Paul M
PM
Guyre
Jose R
JR
Conejo-Garcia
D000954:Antigens, Surface / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002881:Chromosomes, Human, Pair 12; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D055651:NK Cell Lectin-Like Receptor Subfamily B; D010051:Ovarian Neoplasms / Q000276:immunology; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics
D000954:Antigens, Surface; C526358:CLEC2A protein, human; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D008565:Membrane Proteins; D055651:NK Cell Lectin-Like Receptor Subfamily B