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.

The secreted enzyme interleukin four-induced gene 1 (IL4I1) is involved in the negative control of the adaptive immune response. IL4I1 expression in human cancer is frequent and correlates with poor survival and resistance to immunotherapy. Nevertheless, its mechanism of action remains partially unknown. Here, we identified transmembrane serine protease 13 (TMPRSS13) as an immune cell-expressed surface protein that binds IL4I1. TMPRSS13 is a paralog of TMPRSS2, of which the protease activity participates in the cleavage of SARS-CoV-2 spike protein and facilitates virus induced-membrane fusion. We show that TMPRSS13 is expressed by human lymphocytes, monocytes and monocyte-derived macrophages, can cleave the spike protein and allow SARS-CoV-2 spike pseudotyped virus entry into cells. We identify regions of homology between IL4I1 and spike and demonstrate competition between the two proteins for TMPRSS13 binding. These findings may be relevant for both interfering with SARS-CoV-2 infection and limiting IL4I1-dependent immunosuppressive activity in cancer.