Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1

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Science Immunology  24 Jul 2020:
Vol. 5, Issue 49, eabc9492
DOI: 10.1126/sciimmunol.abc9492

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A human immune system sans MAITs

Here, Howson et al. set out to determine the genetic basis of immunodeficiency in a patient with persistent tattoo-associated human papilloma virus–positive warts. Whole-exome sequencing led them to identify a rare point mutation Arg31His (R9H in the mature protein) in both copies of the MR1 gene. MR1 encodes an MHC-like molecule that presents bacteria-derived riboflavin metabolites to mucosal-associated invariant T (MAIT) cells. MAIT cells represent ~5% of circulating human T cells. MAIT cells reside in high frequency in mucosal tissues and provide enhanced immunity against bacterial and viral infections. By solving the structure of the MR1-R9H mutant, they demonstrate that this mutation disrupted the ligand-binding domain of MR1. Consistent with this finding, the individual lacked circulating MAIT cells.


The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.

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