Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3

Pathologic alpha-synuclein (alpha-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic alpha-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by alpha-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of alpha-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by alpha-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for alpha-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic alpha-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson disease and related alpha-synucleinopathies.

Download Full-text

Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa054 ◽

2020 ◽

Vol 14 (10) ◽

pp. 1446-1461 ◽

Cited By ~ 1

Author(s):

Stephanie M Slevin ◽

Lucy C Garner ◽

Conor Lahiff ◽

Malcolm Tan ◽

Lai Mun Wang ◽

...

Keyword(s):

Ulcerative Colitis ◽

T Cells ◽

Disease Activity ◽

Memory T Cells ◽

Lymphocyte Activation ◽

Effector Memory ◽

Cell Numbers ◽

Effector Memory T Cells ◽

Single Cell Rna Sequencing ◽

Lymphocyte Activation Gene

Abstract Background and Aims Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. Methods The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. Results LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. Conclusions LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.

Download Full-text

Biochemical Analysis of the Regulatory T Cell Protein Lymphocyte Activation Gene-3 (LAG-3; CD223)

The Journal of Immunology ◽

10.4049/jimmunol.173.11.6806 ◽

2004 ◽

Vol 173 (11) ◽

pp. 6806-6812 ◽

Cited By ~ 54

Author(s):

Nianyu Li ◽

Creg J. Workman ◽

Stefani M. Martin ◽

Dario A. A. Vignali

Keyword(s):

T Cell ◽

Regulatory T Cell ◽

Biochemical Analysis ◽

Lymphocyte Activation ◽

Cell Protein ◽

Lymphocyte Activation Gene

Download Full-text

Soluble CD30 and Lymphocyte Activation Gene-3 (CD223), as Potential Serological Markers of T Helper-Type Cytokine Response Induced by Acellular Pertussis Vaccine

International Journal of Immunopathology and Pharmacology ◽

10.1177/205873920601900109 ◽

2006 ◽

Vol 19 (1) ◽

pp. 205873920601900 ◽

Cited By ~ 6

Author(s):

C. M. Ausiello ◽

R. Palazzo ◽

F. Spensieri ◽

F. Urbani ◽

M. Massari ◽

...

Keyword(s):

T Cell ◽

Pertussis Vaccine ◽

Lymphocyte Activation ◽

T Cell Responses ◽

Serological Markers ◽

T Helper ◽

Cell Responses ◽

Soluble Cd30 ◽

Vaccine Antigens ◽

Lymphocyte Activation Gene

T cell responses are involved in vaccine-induced immunity to pertussis but no easy-to-monitor, serological markers are available to assess these responses. The lymphocyte activation gene-3 (CD223) molecule is present on, and released by, activated T helper (Th) 1 cells, whereas CD30 molecules have been associated with Th2 immune responses. Starting from the recent knowledge of the cytokine profile induced by pertussis vaccination, we examined the levels of soluble (s)CD223 and sCD30 proteins in child recipients of acellular pertussis (aP) and diphtheria-tetanus (DT) vaccines and in children receiving DT vaccine only, as control. The correlation of the two proteins with specific antibody and T cell responses was assessed. The main findings are: i) sCD223 and sCD30 levels are inversely related, suggesting that the two markers are the expression of different and counter-regulated T-cell responses; ii) sCD30 level correlated with induction of T cell proliferation to pertussis vaccine antigens and antibody response to pertussis toxin. Overall, sCD30 and sCD223 levels seem to be promising candidate markers to assess the induction of Th-type responses in vaccine recipients.

Download Full-text