Regulation of γδ T Cell Effector Diversification in the Thymus

Abstract

γδ T cells are the first T cell lineage to develop in the thymus and take up residence in a wide variety of tissues where they can provide fast, innate-like sources of effector cytokines for barrier defense. In contrast to conventional αβ T cells that egress the thymus as naïve cells, γδ T cells can be programmed for effector function during development in the thymus. Understanding the molecular mechanisms that determine γδ T cell effector fate is of great interest due to the wide-spread tissue distribution of γδ T cells and their roles in pathogen clearance, immunosurveillance, cancer, and autoimmune diseases. In this review, we will integrate the current understanding of the role of the T cell receptor, environmental signals, and transcription factor networks in controlling mouse innate-like γδ T cell effector commitment.

Keywords: IFNγ; IL-17A; TCR signal strength; innate-like lymphocyte; thymus; transcriptional regulation; γδ T cells.

Figure 1

γδ T cell development in the thymus. DN thymocytes undergo γδ-selection and become immature γδ thymocytes that eventually diverge into either IFNγ producers or IL-17A producers. The expression of cell surface markers and transcription factors that define transitional precursors and mature effector γδ T cells are listed next to each cell type. CD24 and CD27 expression at the “effector precursor” stage is heterogenous and is marked by +/–, however, cells transition from CD24⁺ to CD24⁻. DN, double negative; TCR, T cell receptor. Figure made with biorender.com.

Figure 2

Transcription factor network regulating γδ T cell effector programming. Integration of cell surface receptors [TCR, Lymphotoxin Beta Receptor (LTBR), CD27, and Notch] with downstream transcription factors for the programming of γδ T cell effector function. Blue-colored TFs support the type 17 program, while red-colored TFs support the type 1 program. The dotted lines represent indirect regulation or that the supporting data was described in another cell type. The solid lines represent more direct regulation. Figure made with biorender.com.