Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity

Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 ( Lrp10 ) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10 -deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy. Synopsis Lrp10 is a putative cell surface receptor with unknown functions in immunity. This study shows that Lrp10 prevents accumulation of peripheral CD8 T cells, suppresses IL7R expression to limit homeostatic expansion, and impairs anti-tumor immune responses. Genetic deletion of Lrp10 causes an increased number of peripheral CD8 T cells in mice. Lrp10 is induced upon T cell activation and post-translationally suppresses IL7R expression. Lrp10 reduces CD8 central memory differentiation, T cell homeostatic expansion, and IL7 responsiveness. Lrp10 deletion promotes CD8 T cell infiltration, resulting in enhanced anti-tumor immunity and susceptibility to immune checkpoint inhibition. Lrp10 is a putative cell surface receptor with unknown functions in immunity. This study shows that Lrp10 prevents accumulation of peripheral CD8 T cells, suppresses IL7R expression to limit homeostatic expansion, and impairs anti-tumor immune responses.