IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

Abstract

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation in vitro and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses in vitro, thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.

Single-cell analysis revealed that IL4I1 promoted ovarian cancer progression

“…IL4I1 was a secreted L-phenylalanine oxidase expressed by antigen-presenting cells. IL4I1 increased the threshold of T-cell activation, inhibiting T-cell proliferation or differentiation [ 29 , 44 , 47 ], thus influencing immune microenvironment. Imbalance of tumor cell and immune cell might promote cancer progression.…”

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes

“…Indeed, the absence of IL4I1 lowered the activation threshold of cognate CD8 + T cells in a mouse model of acute infection with the lymphocytic choriomeningitis virus, leading to extension of the responding repertoire to low-affinity clones and increased memory T-cell differentiation. Thus, IL4I1 may represent a mechanism to restrain T-cell activation to high-affinity CD8 + T-cell clones (Puiffe et al, 2020).…”

What role for AHR activation in IL4I1-mediated immunosuppression ?

“…We recently dissected the effect of IL4I1 during the priming of naïve CD8 T cells using a model of acute LCMV infection in WT and IL4I1 −/mice. 23 This work revealed unsuspected aspects of IL4I1 action. Somewhat counterintuitively, the effector CD8 T cell response was stronger in WT (IL4I1 + ) mice than in IL4I1 −/mice.…”

“…Genes modulated by 2,3,7,8-tétrachlorodibenzo-p-dioxine (TCDD) in human cells (hepatocytes, CD34 + hematopoietic stem cells, MCF7 and HL60 cell lines) were retrieved from GSE7765, GSE14553, GSE16160, GSE24193, GSE46874, GSE122518 (NCBI GEO site), based on metaanalysis by Oshchepkova et al 22 DCs were obtained by negative cell sorting from spleens of WT and IL4I1 −/mice at steady state and at 24 h of infection with lymphocytic choriomeningitis virus (LMCV) strain WE2.2, as described in Puiffe et al. 23 Mouse experiments were approved by the local Ethical Committee for Animal Experimentation (Cometh Anses/ENVA/UPEC) and the French Research ministry under the number 05338.03.…”

“…Indeed, IL4I1-dependent modulation of the affinity and functional properties of the CD8 T-cell repertoire elicited at priming may interfere with its capacity to combat tumor cells. 23 In this case, IL4I1 effects on early T cell signaling and immune synapse formation are too rapid to involve gene regulation. In particular contexts where sufficient Trp catabolites are generated, IL4I1-mediated AHR activation may play a role in enhancing tumor-cell migration and metastasis, 11 or tumor cell survival, as I3P has also been recently proposed to elicit a cell protective gene expression program.…”