Interplay between Microbiota and γδ T Cells: Insights into Immune Homeostasis and Neuro-Immune Interactions

Abstract

The gastrointestinal (GI) tract of multicellular organisms, especially mammals, harbors a symbiotic commensal microbiota with diverse microorganisms including bacteria, fungi, viruses, and other microbial and eukaryotic species. This microbiota exerts an important role on intestinal function and contributes to host health. The microbiota, while benefiting from a nourishing environment, is involved in the development, metabolism and immunity of the host, contributing to the maintenance of homeostasis in the GI tract. The immune system orchestrates the maintenance of key features of host-microbe symbiosis via a unique immunological network that populates the intestinal wall with different immune cell populations. Intestinal epithelium contains lymphocytes in the intraepithelial (IEL) space between the tight junctions and the basal membrane of the gut epithelium. IELs are mostly CD8⁺ T cells, with the great majority of them expressing the CD8αα homodimer, and the γδ T cell receptor (TCR) instead of the αβ TCR expressed on conventional T cells. γδ T cells play a significant role in immune surveillance and tissue maintenance. This review provides an overview of how the microbiota regulates γδ T cells and the influence of microbiota-derived metabolites on γδ T cell responses, highlighting their impact on immune homeostasis. It also discusses intestinal neuro-immune regulation and how γδ T cells possess the ability to interact with both the microbiota and brain.

Keywords: dysbiosis; inflammation; microbiota; neurotransmitters; γδ T cells.

Figure 1

Classification of intestinal mucosal T cells.

Figure 2

Microbiota regulates the immune response through the Toll-like receptor pathways. Toll-like receptor (TLR) pathways in γδ T cells. MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa B; MAPK: mitogen-activated protein kinase; JNK: c-Jun N-terminal kinases; AP: activator protein 1; TRIF: TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon beta; IRF: interferon-regulatory factor; IP-10: IFN-gamma-inducible protein 10; RANTES: regulated upon activation, normal T cell expressed and secreted, also known as CCL5. Created with BioRender.

Figure 3

Plasticity of γδ T cells. γδ T cells can secrete a wide range of cytokines and chemokines in response to different ligands binding to their corresponding receptors. GPR18: G protein receptor 18; CCR9: C-C chemokine receptor type 9; NKG2A: natural killer group 2 member A; CCR6: C-C chemokine receptor type 6; TLR: toll-like receptor; γδTCR: γδ T cell receptor; IL: interleukin; AhR: aryl hydrocarbon receptor; CD30: also known as TNF receptor superfamily member 8; TGFβ: transforming growth factor β; RegIII: regenerating islet-derived protein 3; KGF: keratinocyte growth factor; IFNγ: interferon γ; TNFα: tumor necrosis factor α; GCSF: granulocytes-colony stimulating factor. Created with BioRender.