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The (inner) world according to GARP: Genetic susceptibility and regulatory T cells

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Science Immunology  07 Aug 2020:
Vol. 5, Issue 50, eabe0976
DOI: 10.1126/sciimmunol.abe0976

Abstract

A human autoimmune and allergic disease susceptibility variant on chromosome 11 results in the reduced expression of the gene encoding the GARP protein and thus compromises the function of regulatory T cells.

There is a human disease risk variant on chromosome 11 that is linked to both autoimmune and allergic diseases. Nasrallah et al. have recently shown that in regulatory T cells, this region at 11q13.5 contains a distal enhancer that regulates the expression of the LRRC32 gene. LRRC32 encodes the GARP (glycoprotein A repetitions predominant) glycoprotein that is important for the function of the cytokine TGF-β1

TGF-β1 has pleiotropic functions but is particularly relevant for regulatory T cell function. TGF-β1 is initially synthesized as a larger inactive homodimer, pro-TGF-β1, that is disulfide-bridged in the endoplasmic reticulum to GARP, an integral membrane glycoprotein. This pro-TGF-β1–GARP complex is transported to the cell surface where GARP holds the latent pro-TGF-β1 on the plasma membrane. There, pro-TGF-β1 is cleaved by furin to yield a C-terminal mature TGF-β1 homodimer and an N-terminal dimeric piece that is called the latency associated peptide, or LAP. Even after furin cleavage, mature TGF-β1 remains associated with and “embraced” by LAP, which in turn is still attached to GARP. TGF-β1 therefore remains in an inactive or latent form even after maturation but needs to be released from its embrace by LAP.

On most cells other than Tregs, GARP presents the inactive mature TGF-β1–LAP complex to an integrin called αvβ6 that grabs LAP and physically detaches it from mature TGF-β1. This prising away of LAP from TGF-β1 is how this cytokine is activated. Although Tregs lack the expression of αvβ6, they express a different integrin called αvβ8, which does the job of releasing mature TGF-β1 from LAP in order to activate it.

Nasrallah and colleagues identified a transcriptional enhancer at 11q13.5 that is required for GARP expression specifically in regulatory T cells. By deleting this enhancer region in mice, the expression of GARP was specifically lost in Tregs, and the mice developed a severe colitis. Individuals with the risk variant had reduced expression of GARP. A CRISPR-based strategy was also used to confirm the relevance of this enhancer to the expression of GARP in human Tregs. GARP keeps our inner world in balance and disease at bay.

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