Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity

Abstract

Extended Data Fig. 6 | Cd4-driven Cre recombinase expression efficiently deletes CD39 on CD8 + TIL. (a, b) TIL analysis of CD39 and inhibitory expression in CD8 + T cells from Cd4 Cre Entpd1 f/f mice. (c) Cell counts per milligram of tumor mass from experiments in Extended Data Fig. 6a, b. (d) Tumor areas at day 14 from experiments in Fig. 2f. (e) Suppression assay of Cd4 Cre Entpd1 f/f Thy1.1 + CD44 + OT-I T eff cells isolated from day 8 of acute Vaccinia OVA infection. (f) CD39 expression on TIL tT ex cells or Vaccinia OVA OT-I T cells in suppression assay co-cultures. (g) Suppression assay of B16-F10-derived CD8 + tT ex cells co-cultured with OT-I TCR transgenic CD8 + T cells. Culture were stimulated with either anti-CD3 antibodies as before, or OT-I specific peptide, SIIFEKL. (h-j) Flow cytometric analysis of TIL following suppression assay from Extended Data Fig. 6g. Statistics are Mann-Whitney (B-D,H-J) and linear regression (E,G) with * p < 0.05, * * p < 0.01,

Multi-Omics Atlas-Assisted Discovery of Transcription Factors for Selective T Cell State Programming

“…2D). Indeed, recently Vignali et al reported the connection of hypoxia and exhaustion that support the accuracy of our bioinformatics analysis (47). Furthermore, this systemic analysis indicated shared TFs can be a molecular basis of the parallel differentiation trajectories, Naive → MP → TRM and Naive → TexProg → TexTerm, from acute and chronic infection (fig.…”

Extra-islet expression of islet antigen boosts T-cell exhaustion to prevent autoimmune diabetes

“…Indeed, it has been shown that exhausted T cells are not only hypofunctional but can also upregulate molecules that suppress local T cell immunity. Exhausted T cells upregulate CD39 and IL-10 which are both important molecules utilised by regulatory T cells (Tregs) to mediate suppressive functions(31, 32). Consistent with this idea, IGRP-specific cells in NOD-TII mice expressed high levels of IL-10 (Fig 6B) and CD39 (Fig 6C and D), while there was no difference in the frequency of FoxP3 + Tregs between NOD and NOD-TII mice (Fig 6E).…”

“…CD39 ( Entpd1 ) is expressed in terminally exhausted T cells (40) and acts via catabolising ATP and ADP to AMP and further degradation to adenosine via CD73. A recent study has shown that CD39 expressing terminally exhausted cells have suppressive capacity similar to conventional FoxP3 expressing CD4+ regulatory T cells(31). Several reports have identified that IL-10 secreting CD8 + T cells play a regulatory role in protecting against autoimmune disease (32, 41, 42).…”

Theranostics on the immunoactivity of T cells

“…4 There are many other factors, such as, resistance of targeted cells, metabolic status, hypoxia, etc., may also affect the tempo of exhaustion. 5 Other methods include adoptive T-cell therapy, in which T cells are extracted from the patient, modified, expanded in vitro, and then infused back into the patient to boost their antitumour capabilities. 6,7 Unfortunately, the broad effectiveness of T cell-based cancer therapy in the clinic is still elusive.…”

“…Despite these important advances, only certain subsets of T cells could be reinvigorated 4 . There are many other factors, such as, resistance of targeted cells, metabolic status, hypoxia, etc., may also affect the tempo of exhaustion 5 . Other methods include adoptive T‐cell therapy, in which T cells are extracted from the patient, modified, expanded in vitro, and then infused back into the patient to boost their antitumour capabilities 6,7 .…”