An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment

Summary Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability.
Graphical Abstract
Highlights • Memory Tregs can be classified as T helper-like Tregs (Th2, Th17, Th1, and Th1/17) • Human Th2-like Tregs exhibit the highest viability and IL-2-mediated activation • Th2-like Tregs are the subset with the highest chemotaxis toward CCL17/22 • Th2-like Tregs are enriched at tumor sites in melanoma and colorectal cancer
Halim et al. provide a comprehensive transcriptomic and functional analysis of circulating Th-like Tregs, revealing unique features in Th2-like Tregs and a significant enrichment of this subset in patients with melanoma and colorectal cancer. This suggests that Th2-like Tregs play a major role in maintaining a tumorigenic environment.