Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226

Abstract

Regulatory T cells (Treg) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Treg (tTreg) and CD4+FOXP3+Helios− T cells, followed by comparison to CD4+FOXP3−Helios− T conventional (Tconv) cells. These analyses revealed that the coinhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4+CD25+CD127lo/− T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Treg following activation and in vitro expansion and is associated with lineage stability and suppressive capacity. Conversely, the CD226+TIGIT− population was associated with reduced Treg purity and suppressive capacity following expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Treg in health and disease.

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

“…However, the inverse correlation between IL-10 production and the Treg signature genes in our analysis is consistent with the recent report on human Treg cells in which IL-10 expression is inversely correlated with the Foxp3 and Helios expression (45). In addition, unlike the observation in mice, we were not able to demonstrate any correlation between a typical Th-specific transcription factor and the suppression of Th-specific cytokines (Fig.…”

TIGIT predominantly regulates the immune response via regulatory T cells

“…Thus, TIGIT signaling in Tregs may favor Treg stability. In line with this observation, TIGIT expression has recently been shown to correlate strongly with a stable Treg phenotype in humans (14). Importantly, several of the Figure 3A and Supplemental Table 1).…”

“…Interestingly, while TIGIT + CD8 + TILs exhibited deficits in proinflammatory cytokine production, we found that they had significantly increased production of the immune-suppressive cytokine IL-10 compared with TIGIT -CD8 + TILs. Moreover, we found that TIGIT + CD8 + TILs exhibited a reduced capacity to degranution to direct regulation of effector T cell responses, recent studies show that TIGIT marks a subset of Tregs that exhibit heightened expression of known Treg effector molecules and heightened suppressive capacity in vitro (12,14). Most interestingly, TIGIT + Tregs exhibit a specialized function, that of selectively suppressing proinflammatory Th1 and Th17 responses but sparing Th2 responses (12), thus supporting a role for TIGIT in directing Treg function.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…It is now clear that much complexity in the Treg phenotype exists than originally appreciated, and a growing number of other cell surface markers are found on specific Treg subsets, for example TIGIT,11, 12 GARP,13, 14, 15, 16 CD73 and CD39 17, 18. These markers are frequently also found on effector cell populations, and an emerging theme is that either Treg are able to transition between functional states or that the Treg compartment is paired with the Tconv effector compartment so that any immune response mediated by a T‐cell can be controlled by a matching Treg 19.…”