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This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (Milan, Italy) and the European Community (Cancer Immunotherapy, Contract No. 518234).

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LAG-3 Expression Defines a Subset of CD4(+)CD25(high)Foxp3(+) Regulatory T Cells That Are Expanded at Tumor Sites

Publicado en:JOURNAL OF IMMUNOLOGY. 184 (11): 6545-6551 - 2010-06-01 184(11), DOI: 10.4049/jimmunol.0903879

Autores: Camisaschi, Chiara; Casati, Chiara; Rini, Francesca; Perego, Michela; De Filippo, Annamaria; Rini, Frederic; Parmiani, Giorgio; Belli, Filiberto; Rivoltini, Licia; Castelli, Chiara;

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Resumen

Human natural regulatory CD4(+) T cells comprise 5-10% of peripheral CD4(+) T cells. They constitutively express the IL-2R alpha-chain (CD25) and the nuclear transcription Foxp3. These cells are heterogeneous and contain discrete subsets with distinct phenotypes and functions. Studies in mice report that LAG-3 has a complex role in T cell homeostasis and is expressed in CD4(+)CD25(+) T regulatory cells. In this study, we explored the expression of LAG-3 in human CD4(+) T cells and found that LAG-3 identifies a discrete subset of CD4(+)CD25(high)Foxp3(+) T cells. This CD4(+)CD25(high)Foxp3(+)LAG-3(+) population is preferentially expanded in the PBMCs of patients with cancer, in lymphocytes of tumor-invaded lymph nodes and in lymphocytes infiltrating visceral metastasis. Ex vivo analysis showed that CD4(+)CD25(high)Foxp3(+)LAG-3(+) T cells are functionally active cells that release the immunosuppressive cytokines IL-10 and TGF-beta 1, but not IL-2. An in vitro suppression assay using CD4(+)CD25(high)Foxp3(+)LAG-3(+) T cells sorted from in vitro expanded CD4(+)CD25(high) high regulatory T cells showed that this subset of cells is endowed with potent suppressor activity that requires cell-to-cell contact. Our data show that LAG-3 defines an active CD4(+)CD25(high)Foxp3(+) regulatory T cell subset whose frequency is enhanced in the PBMCs of patients with cancer and is expanded at tumor sites. The Journal of Immunology, 2010, 184: 6545-6551.

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