Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo.
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.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Nicholas M
NM
Durham
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Christopher J
CJ
Nirschl
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Christopher M
CM
Jackson
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Jimmy
J
Elias
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Christina M
CM
Kochel
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Robert A
RA
Anders
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Charles G
CG
Drake
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse