Thymic Program Directing the Functional Development of γδT17 Cells

Abstract

γδT cells comprise a unique T cell sublineage endowed with a wide functional repertoire, which allow them to play important-sometimes opposite-roles in many immune responses associated with infection, cancer, and inflammatory processes. This is largely dependent on the existence of pre-programmed discrete functional subsets that differentiate within the thymus at specific temporal windows of life. Since they represent a major early source of interleukin-17A in many models of immune responses, the γδT17 cell population has recently gained considerable interest. Thus, a better dissection of the developmental program of this effector γδT subset appears critical in understanding their associated immune functions. Several recent reports have provided new exciting insights into the developmental mechanisms that control γδT cell lineage commitment and differentiation. Here, we review the importance of thymic cues and intrinsic factors that shape the developmental program of γδT17 cells. We also discuss the potential future areas of research in γδT17 cell development especially in regards to the recently provided data from deep RNA sequencing technology. Pursuing our understanding into this complex mechanism will undoubtedly provide important clues into the biology of this particular T cell sublineage.

Keywords: development; innate immunity; interleukin-17A; thymus; transcription factor; γδT cells.

Figure 1

Overview of thymic γδT17 cell ontogeny. Initial intrathymic pathways leading to pre-committed γδT17 cells divergence from other T cell lineages are illustrated. The thymic (cortical and medullary) environmental cues involved in γδT17 cell effector fate and the preferential peripheral niches of mature γδ17 cells are also depicted. Labels indicate the cells, soluble factors, proteins, surface markers, and T cell receptor (TCR) signal strength involved in the γδT17 cell program of differentiation.

Figure 2

Schematic overview of the current knowledge in the transcription factor (TF) network involved in natural γδT17 cell effector fate. Major activating and repressing pathways implicated during γδ17 effector fate acquisition are depicted.

Figure 3

Volcano plots of the top 1,000 regulated genes during Vγ6 and Vγ5 maturation. Raw data were extracted from datasets (GSE37448 and GSE15907) downloaded from the NCBI’s data repositories. Vγ6⁺ and Vγ5⁺ gene sets were generated by comparing gene expression in immature (CD24^high) vs mature (CD24^low) thymocytes at E17 for both populations (2–3 replicates/subset). The top 1,000 regulated genes (P < 0.05) were used to constitute the two gene sets (Table S1 in Supplementary Material). Volcano plots represent either positively or negatively regulated genes (as fold change) according to their respective P value. Labels indicate the percentage of genes that are either positively or negatively regulated in each dataset. FC, fold change.

Figure 4

Proposed new biological pathways involved in intrathymic Vγ6⁺ maturation. Biological pathways with enriched modulated genes in the Vγ6⁺ dataset are represented based on advanced pathway analysis using the trial version of iPathwayGuide (©Advaita Corporation).