Degraded into Anergy

Science's STKE  09 Mar 2004:
Vol. 2004, Issue 223, pp. tw84-TW84
DOI: 10.1126/stke.2232004TW84

T cells can respond positively to stimuli or can become inactivated, which produces a state called anergy. Anergy is essential to the body's ability to recognize self antigens and not mount autoimmune responses. Calcium is a key regulator of the T cell response, and calcium stimulates gene expression through activation of calcineurin, a calcium-stimulated phosphatase, and the transcription factor NFAT. Heissmeyer et al. showed that sustained elevation of calcium by exposure of T cells to ionophore or by stimulation in the absence of a costimulatory signal led to an anergic state associated with increased expression of several genes, including some involved in ubiquitin-mediated degradation. The latter included the E3 ubiquitin ligases, Itch, Cbl-b, and GRAIL, and the ubiquitin-binding protein Tsg101 of the ESCRT-1 endosomal sorting complex. Cells that became anergic showed decreased levels of phospholipase C-γ1 (PLC-γ1), protein kinase C isoform θ (PKC-θ), and the guanosine triphosphatase-activating protein Ras-GAP. The decrease in these proteins was blocked by the calcineurin inhibitor cyclosporin A. The decrease was most pronounced when the cells were challenged with a stimulatory signal after the anergy-inducing treatment. PLC-γ1 and PKC-θ were confirmed to be ubiquitinated in anergic cells; however, their stability was not enhanced by inhibition of the proteasome. This is consistent with the induction of the expression of the Tsg101 gene, the product of which mediates lysosomal targeting of monoubiquitinated proteins for degradation. Interestingly, the anergic T cells exhibited unstable immunological synapses when exposed to antigen-presenting cells. This instability could be reproduced in normal T cells by pharmacological inhibition of PLC. T cells from mice deficient in Itch or Cbl-b exhibited an inability to become anergic and showed highly stable immunological synapses after treatments that should have produced a state of anergy.

V. Heissmeyer, F. Macián, S.-H. Im, R. Varma, S. Feske, K. Venuprasad, H. Gu, Y.-C. Liu, M. L. Dustin, A. Rao, Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat. Immunol. 5, 255-265 (2004). [Online Journal]