Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

Abstract

Data have been reported on the in vivo adjuvant role of soluble lymphocyte activation gene-3 (LAG-3) recombinant protein in mouse models and on its ability to support the in vitro generation of human, tumor-specific CTLs. In this study, we show that soluble human rLAG-3 protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promoted the production of chemokines and TNF-α inflammatory cytokine. When given in association with optimal or suboptimal doses of CD40/CD40L, hLAG-3Ig functions as a strong costimulatory factor and induces full functional activation of monocyte-derived dendritic cells that includes the production of high level of IL-12p70. Moreover, evidence is here provided that this costimulatory function licensing dendritic cells to produce IL-12p70 is also a functional property of LAG-3 molecules when expressed in a physiological context by CD4+ activated T cells. Altogether, these data show for the first time a role of LAG-3 in mediating dendritic cell activation when expressed on the T cell surface or released after specific Ag stimulation in the interspaces of immunological synapses.

CTLA‐4 is required by CD4+CD25+ Treg to control CD4+ T‐cell lymphopenia‐induced proliferation

“…There was however a marked increase in the expression of LAG3 by KO Treg. Although LAG3 negatively regulates T cell function, in its soluble form it can have stimulatory properties on dendritic cells [18]. Thus over-expression of LAG3 by KO Treg may activate APC to enhance, rather than suppress, expansion of CD4+ T cells in the lymphopenic environment.…”

Cancer Immunotherapy: The Role Regulatory T Cells Play and What Can be Done to Overcome their Inhibitory Effects

“…Further, this same group showed that antibodies to LAG-3 could inhibit the suppressive function of Treg cells. In contrast to studies in mice, in humans soluble LAG-3 protein can promote a TH1 immune responses, a response that is generally appreciated to be therapeutic in a majority of tumor models (44). Additional investigations will be required to determine the role for LAG-3 in generating DC that are suppressive or promote the development of a therapeutic immune response.…”

Enrichment of LAG-3, but not PD-1, on Double Negative T Cells at the Female Genital Tract

“…LAG‐3 is poorly expressed on peripheral lymphocytes, but can be expressed on recently activated T cells . In addition to inhibiting T‐cell function, binding of MHCII by LAG‐3 initiates APC maturation pathways and promotes IL‐12 and TNF‐α production . LAG‐3 expression at the genital mucosa could, therefore, play a role in antigen processing and innate immunity to sexually transmitted infections and normal flora by modulating immune activation at the FGT.…”