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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere109080
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 5 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Durham, N. M., Nirschl, C. J., Jackson, C. M., Elias, J., Kochel, C. M., Anders, R. A., & Drake, C. G. (2014). Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed In Vivo. PloS one, 9(11), [e109080]. https://doi.org/10.1371/journal.pone.0109080