LAG-3 Expression and Functional Activities in Tumor-Specific T Cells
Posted on: Thursday, 17 June 2004, 06:00 CDT
LAG-3 (Lymphocyte Activation Gene-3) is a member of Ig super family genetically and structurally related to CD4. LAG-3 protein is expressed in activated CD4^sup +^ and CDS^sup +^ T lymphocytes and in NK cells and binds MHC class II molecules with a higher affinity than CD4. Several studies in murine and in human setting suggest a complex role of LAG-3 in controlling T cell functions. The aim of our study was to dissect the active involvement of LAG-3 molecule in shaping the tumor-specific immune response. We first investigated the role of LAG-3 molecule in modulating the effector functions of LAG-3-positive melanoma-specific T cell clones upon stimulation with their nominal antigens. The addition of neutralizing anti-LAG-3 antibody in the recognition assay leads to an enhancement of T cell stimulation induced by the autologous tumor, as assessed by cytokine release. Although stained positive for LAG-3, no functional activity was detected for this molecule in CDS+ anti-tumor T cells. All together these data confirm a possible negative role of LAG-3 in regulating the final effector functions of tumor-specific CD4^sup +^T cell clones. Due to challenging parallels existing between LAG- 3 and CTLA-4, an additional crucial negative regulator of T cells, which may play a role in the functions of T regulatory cells, we analyzed the LAG-3 expression in CD25^sup +^ CD4^sup +^ and CD25- CD4^sup +^ T cells of peripheral blood of healthy donors. The expression of LAG-3 protein in PBL ranged from 1 to 6% with some exception reaching an unusual 23%, while LAG-3 expression on CD25^sup +^ or CD25-gated populations varied from donor to donor, but higher in the CD25^sup +^ population in the majority of them. Furthermore, after in vitro activation with allogeneic DC, the percentage of LAG-3 positive cells were significantly increased reaching the 30-40 % of positive cells in both CD4^sup +^CD25^sup +^ and CD4^sup +^CD25- population upon in vitro allostimulation. Therefore we conclude that LAG-3 protein, although is preferentially expressed in CD4^sup +^ CD25^sup +^ fraction in peripheral blood of healthy donors, cannot be considered as a specific marker of this cell subset.
C. Casati1, F. Rini1, F. Arienti2, L. Rivoltini1, F. Triebel3, G. Parmiani1, C. Castelli1
1 Unit of Immunotherapy of Human Tumors, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; 2 Immunohematology and Transfusion Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; 3 Equipe d'Accueil 3545, Faculte de Pharmacie, Chatenay-Malabry, France
Copyright Edizioni Minerva Medica Mar 2004
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