# The early human interferon gamma response to Toxoplasma gondii is driven by Vγ9Vδ2 T-cell sensing of host phosphoantigens and subsequent NK-cell activation

## TL;DR

The human immune system detects Toxoplasma gondii through Vγ9Vδ2 T cells, which activate other immune cells to fight the parasite early in infection.

## Contribution

This study identifies Vγ9Vδ2 T cells as key drivers of the early human immune response to Toxoplasma gondii.

## Key findings

- Vγ9Vδ2 T cells are activated by Toxoplasma-infected cells via the BTN3A1 receptor, leading to IFNγ and TNFα secretion.
- These T cells enhance NK cell IFNγ production through TNFα and IL-12 during infection.
- Parasite invasion increases host phosphoantigens, and blocking the mevalonate pathway reduces the immune response.

## Abstract

Toxoplasma gondii is a globally prevalent intracellular parasite that infects ~40 million Americans. The murine immune response to Toxoplasma relies on both toll-like receptor (TLR) 11/12 and immunity related GTPase-mediated (IRGs) responses, which humans lack, making it unclear how the human immune response detects and responds to the parasite. We investigated whether human Vγ9Vδ2 T cells, which detect phosphoantigens through the BTN3A1 receptor, shape the early immune response to the parasite. Using primary human peripheral blood mononuclear cells (PBMCs), we show that Vγ9Vδ2 T cells are activated by Toxoplasma-infected cells in a BTN3A1-dependent manner leading to secretion of interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNFα). Additionally, these T cells potentiate IFNγ production by natural killer (NK) cells, via TNFα and interleukin (IL)-12 produced during infection. Active parasite invasion is required to stimulate the IFNγ response, and inhibition of the host mevalonate pathway, which limits the synthesis of the phosphoantigen isopentenyl pyrophosphate (IPP), attenuates the cytokine response, indicating Toxoplasma infection increases host phosphoantigens leading to Vγ9Vδ2 T cell activation. Our findings identify Vγ9Vδ2 T cells as key effectors that potentiate NK cells in the early human immune response to Toxoplasma, bridging innate and adaptive immunity in the absence of TLR11/12 signaling.

Toxoplasma gondii is a common parasite that infects about one third of the world’s population. Most healthy people do not get sick, but infection can cause severe disease in unborn babies and people with weak immune systems. We wanted to know how the human immune system detects this parasite early during infection. Because mice rely on sensors that humans do not have, we focused on a human specific group of T cells called V gamma 9 V delta 2 T cells. We found that these cells respond to infection by producing interferon gamma, a signaling protein that helps other immune cells control the parasite. This early response occurs when infection alters a pathway that cells use to make cholesterol and other lipids, called the mevalonate pathway. These changes increase small phosphorus containing molecules that are detected by an internal region of the immune cell membrane protein butyrophilin 3A1. Once activated, V gamma 9 V delta 2 T cells also make tumor necrosis factor and help natural killer cells produce more interferon gamma, forming an early immune circuit that likely strengthens human resistance to Toxoplasma.