Glucocorticoid-induced leucine zipper is a primary checkpoint molecule that establishes a virus-specific CD8+ T-cell activation threshold

Bennett, TJ; Lam, C; O&#39;Hara, J; Udupa, VAV; Thiele, D; Lee, JKC; Barugahare, A; Li, J; La Gruta, NL; Jones, SA; Russ, BE; Turner, SJ

Author(s): Bennett, TJ; Lam, C; O'Hara, J; Udupa, VAV; Thiele, D; Lee, JKC; Barugahare, A; Li, J; La Gruta, NL; Jones, SA; Russ, BE; Turner, SJ;
Details: Publication Year 2026-02-09,Volume 215,Issue #2,Page vkaf353
Journal Title: Journal of Immunology
Publication Type: Research article
Abstract: Naïve CD8+ T-cell activation needs to overcome a signaling threshold to initiate the resulting program of T cell proliferation and differentiation. While the strength of T-cell receptor (TCR) signaling and co-stimulation are known to dictate T-cell responsiveness, the role of other factors that determine strength of signal is not well studied. Glucocorticoid-induced leucine zipper (GILZ) is a regulatory protein that serves to dampen activation signals in several leukocyte populations. Here we demonstrate that GILZ is highly expressed in murine naïve CD8+ T cells and downregulated with activation. GILZ deficiency increased accumulation of antigen-specific CD8+ T-cell responses in a mouse model of influenza A virus infection, and this correlated with greater responsiveness to low-affinity ligands. GILZ-deficient CD8+ T cells were able to better engage optimal effector transcriptional programs at lower signaling thresholds, highlighting GILZ as a key checkpoint for naïve CD8+ T cell activation. Importantly, GILZ deficiency did not impact memory T cell formation or recall responses to influenza A virus infection. These data demonstrate that GILZ acts as an important naïve CD8+ T cell checkpoint by establishing a threshold for initial activation. Modulation of GILZ could be beneficial in improving CD8+ T cell responses against low-affinity ligands, particularly like those found in the context of tumor antigens.
Publisher: Oxford University Press
Keywords: CD8+ T cell; T-cell memory; influenza virus; transcription factor
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1093/jimmun/vkaf353
Open Access at Publisher's Site: https://doi.org/10.1093/jimmun/vkaf353
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-03-05 03:10:33

Last Modified: 2026-03-05 03:10:47