# Immuno-functionomics reveals geographical variation and a role for TLR8 in mRNA vaccine responses

## TL;DR

This study shows how the innate immune system varies across populations and identifies TLR8 as important for mRNA vaccine responses.

## Contribution

A new method called immuno-functionomics was developed to measure immune function across multiple cell types and receptors.

## Key findings

- Rural Indonesians showed higher IL-1β and lower IFNγ production compared to urban Indonesians and Europeans.
- Baseline IFNγ production in Europeans correlated with stronger mRNA-1273 vaccine responses.
- In vitro mRNA vaccine responses depend on TLR8 and are reduced in rural Indonesians.

## Abstract

The innate immune system plays a pivotal role in pathogen defense via pattern recognition receptor sensing, initiating responses upon infection or vaccination. Understanding its functional capacity is crucial for deciphering correlates of vaccine efficacy and understanding responses to infection. Here, we developed a holistic approach to study immune function, generating >3,100 readouts across 16 cell types, 18 pattern recognition receptors, and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we compared Europeans and urban and rural Indonesians. We observed different immune responses, such as increased interleukin (IL)-1β production in rural Indonesians and impaired interferon (IFN) γ production by innate lymphocytes after Toll-like receptor (TLR) 8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFNγ production by innate lymphocytes correlated with SARS-CoV-2 spike-specific immune responses. In vitro mRNA vaccine stimulation also induced IFNγ production, which was TLR8 dependent and reduced in rural Indonesians. This study highlights functional immune diversity and TLR8’s potential role in mRNA vaccine responses.

•Spectral flow assay maps innate immune function across 16 cell types using 18 PRR sensors•Innate responses in rural Indonesians differ from those in urban Indonesians and Europeans•Baseline TLR8-driven capacity correlates with spike-specific mRNA-1273 responses•In vitro innate lymphocyte responses to mRNA vaccines depend on TLR8 sensing

Spectral flow assay maps innate immune function across 16 cell types using 18 PRR sensors

Innate responses in rural Indonesians differ from those in urban Indonesians and Europeans

Baseline TLR8-driven capacity correlates with spike-specific mRNA-1273 responses

In vitro innate lymphocyte responses to mRNA vaccines depend on TLR8 sensing

Health sciences; Medicine; Medical specialty; Immunology