Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo
Nicholas M Durham, Christopher J Nirschl, Christopher M Jackson, Jimmy Elias, Christina M Kochel, Robert A Anders, Charles G Drake, Nicholas M Durham, Christopher J Nirschl, Christopher M Jackson, Jimmy Elias, Christina M Kochel, Robert A Anders, Charles G Drake
Abstract
Lymphocyte Activation Gene - 3 (LAG-3) is an immune checkpoint molecule that regulates both T-cell activation and homeostasis. However, the molecular mechanisms underlying LAG-3's function are generally unknown. Using a model in which LAG-3 blockade or absence reliably augmented homeostatic proliferation in vivo, we found that IL-2 and STAT5 are critical for LAG-3 function. Similarly, LAG-3 blockade was ineffective in the absence of regulatory T-cells (Treg), suggesting an important role for LAG-3 in either the responsiveness of conventional T-cells (Tconv) to regulation, or a relative defect in the ability of LAG-3 KO regulatory T-cells (Treg) to suppress the proliferation of Tconv. In this model, LAG-3 KO Treg suppressed proliferation in a manner fairly similar to wild-type (WT) Treg, but LAG-3 KO Tconv were relatively resistant to suppression. Further studies also identified a role for LAG-3 in the induction/expansion of Treg. Finally, we found that LAG-3 blockade (or knockout) led to a relative skewing of naïve CD4 T-cells toward a TH1 phenotype both in vitro and in in vivo. Together, these data suggest that LAG-3 expression on Tconv cells makes them more susceptible to Treg based suppression, and also regulates the development of a TH1 T-cell response.
Conflict of interest statement
Competing Interests: CGD has served as a paid consultant for Bristol Myers Squibb, Compugen and Roche/Genentech. CGD is a co-inventor on a patent entitled: “Manipulation of Regulatory T Cells Using LAG-3 Antibodies, Genes, Agonists and Antagonists”, filing case number: C04255. This patent is currently un-licensed. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
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References
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