Details

Autor(en) / Beteiligte

• Previte, Dana M.
• Martins, Christina P.
• O’Connor, Erin C.
• Marre, Meghan L.
• Coudriet, Gina M.
• Beck, Noah W.
• Menk, Ashley V.
• Wright, Rebecca H.
• Tse, Hubert M.
• Delgoffe, Greg M.
• Piganelli, Jon D.

Titel

Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4+ T Cells

Ist Teil von

• Cell reports (Cambridge), 2019-04, Vol.27 (1), p.129-141.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed by CD4+ T cells and tempers their homeostatic expansion. Because CD4+ T cell proliferation is tightly coupled to bioenergetics, we investigate the role of LAG-3 in modulating naive CD4+ T cell metabolism. LAG-3 deficiency enhances the metabolic profile of naive CD4+ T cells by elevating levels of mitochondrial biogenesis. In vivo, LAG-3 blockade partially restores expansion and the metabolic phenotype of wild-type CD4+ T cells to levels of Lag3−/− CD4+ T cells, solidifying that LAG-3 controls these processes. Lag3−/− CD4+ T cells also demonstrate greater signal transducer and activator of transcription 5 (STAT5) activation, enabling resistance to interleukin-7 (IL-7) deprivation. These results implicate this pathway as a target of LAG-3-mediated inhibition. Additionally, enhancement of STAT5 activation, as a result of LAG-3 deficiency, contributes to greater activation potential in these cells. These results identify an additional mode of regulation elicited by LAG-3 in controlling CD4+ T cell responses. [Display omitted] •LAG-3 limits CD4+ T cell oxygen consumption and spare respiratory capacity (SRC)•Naive CD4+ T cells utilize their SRC to support spontaneous proliferation•LAG-3 regulates STAT5 and Akt activation•Lag3−/− CD4+ T cells are less dependent upon IL-7 for survival and metabolism Previte et al. show that LAG-3 expression regulates the metabolic profile of naive CD4+ T cells during homeostatic expansion. They observed that Lag3-deficient CD4+ T cells are resistant to Interleukin-7 deprivation due to enhanced STAT5 activation. Increased STAT5 signaling also mediated greater activation potential in these T cells following stimulation.