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.
Highlights
The negative control of T-cell responses is regulated by multiple factors, including amino-acid catabolizing enzymes
We describe the differentiation of CD8 T cells from the endogenous repertoire and from the transgenic P14 clone in IL4-induced gene 1 (IL4I1)-competent and IL4I1-deficient mice after in vivo priming by an acutely cleared infection with lymphocytic choriomeningitis virus (LCMV)
We show that the absence of IL4I1 is paradoxically associated with diminished expansion of TSLE that produce effector cytokines and granzyme B
Summary
The negative control of T-cell responses is regulated by multiple factors, including amino-acid catabolizing enzymes. These enzymes regulate the availability of essential or semi-essential amino acids in the proximal environment of T cells and produce bioactive metabolites with proapoptotic or antiproliferative effects. IL4-induced gene 1 (IL4I1) is an L-phenylalanine oxidase that produces phenylpyruvate, hydrogen peroxide, and ammonia [1]. It limits the activation and proliferation of T cells and modulates CD4 T-cell differentiation, at least partially, through its enzymatic activity. IL4I1 is focally secreted by antigen-presenting cells in the synaptic cleft and attaches to the T cell [2].
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