Inhibition of LARP4-mediated quiescence exit of naive CD4+ T cells ameliorates autoimmune and allergic diseases

Abstract

Naive T cells are maintained under a quiescent state, and their exit from quiescence is a hallmark of antigen stimulation. Here we identify the RNA binding protein La-related protein 4 (LARP4) as an important checkpoint regulator of quiescence exit in naive CD4⁺ T cells. Conditional knockout of LARP4 in naive CD4⁺ T cells leads to an enhanced quiescence state and/or dampened quiescence exit due to altered stability of several messenger RNAs important for T-cell activation. The differentiation of naive CD4⁺ T cells into helper T-cell subsets is also impaired after conditional knockout, leading to ameliorated autoimmune and allergic responses. Lastly, we design a peptide inhibitor of LARP4 (LIPEP), and treatment with LIPEP could perfectly mimic LARP4 deficiency and alleviate the severity of autoimmune and allergic diseases in the corresponding mouse models. Our study reveals a link between RNA stability and CD4⁺ T-cell homeostasis/adaptive activation, highlighting the potential of LARP4 as a preventative and therapeutic target for autoimmune and allergic diseases although at quite high doses.