In 2001, many investigations discovered and characterized human regulatory T cells (Tregs) as CD4+ CD25high T cells [1]. Tregs suppress the growth, stimulation, and production of cytokines of CD8+ T cells, B cells, antigen-presenting cells (APCs), and natural killer (NK) cells in addition to other CD4+ T cells [2]. Considered to be the “master regulator” responsible for Treg creation and operation, Forkhead box P3 (FoxP3) is the traditional and distinctive marker of Treg cells [3]. It is important to note that there have been reports of several inhibitory regulatory T cell types, including NKT cells, CD8+ cells, Type 1 regulatory cells or Tr1 (TR1), T helper 3 cells (Th3), and peripherally generated Tregs [4]. These cells acquire their repressive properties due to certain cytokines or stimulating circumstances. On the other hand, human FoxP3+ natural Tregs primarily develop their unique inhibitory capabilities in the thymus [5], [6].

According to in vitro research, human Tregs can suppress traditional responder T cells by several mechanisms, including direct cell-to-cell interaction and the release of inhibitory cytokines [7]. Human Treg suppression requires TCR activation and co-stimulation (usually of CD28 or CD2), which can be carried out in an APC-free environment or the presence of APCs [8]. Different strategies for suppressing human Treg are available, including Granzymes A and B [9], [10], adenosine [11], CD95-CD95L [12], and IL10 [13]. Their strategies are similar to but distinct from, the mice Treg suppressive mechanisms. Surprisingly, inhibiting capability disappears if TCR and co-stimulatory molecule stimulating are too high or if inflammatory mediators are added to the suppression assay [14]. This is probably because of a mixture of reduced Treg inhibitory function and raised responder T cell resistance to inhibition [14], [15], [16], [17]. To enable conventional T cells to fight infections without being impeded by Treg suppression, it may be advantageous to have proinflammatory, highly stimulating conditions that can reverse human Treg suppression. However, these conditions would not be suitable for treating autoimmune illnesses [18], [19].

Long non-coding RNAs (lncRNAs), defined as more than 200 nucleotides, make up the majority of the transcriptome and have been identified as a significant component of the mammalian transcriptome by the Encyclopedia of DNA Elements (ENCODE) and Functional Annotation of the Mammalian Genome (FANTOM) projects [20], [21]. About 20,000 human lncRNAs with functional insight have also been found, according to a study that summarized many transcript collections [22]. In fact, the majority of the single-nucleotide polymorphisms (SNPs) linked to diseases or traits found through genome-wide association studies (GWASs) are found in the non-coding region [23], indicating that both lncRNAs and DNA regulatory elements may have functional roles in a variety of diseases. lncRNAs are located in the cytoplasm or nucleus of cells and are produced by RNA polymerase II by transcription from DNA [24]. Exons and introns make up lncRNAs, which may form secondary structures that enable them to make contact with other substances including proteins, RNA, and DNA [25], [26]. Their integrity and activity can also be changed by post-transcriptional modifications like as splicing, capping, and polyadenylation [24].

Differentiation and development are two biological functions that have been connected to lncRNAs. They have been found to play important roles in the formation of many organs and tissues, as well as in the regulation of stem cell transcription [27], [28], [29]. Numerous diseases, including cardiovascular disorders [30], [31], [32], [33], [34], [35], [36], neurological conditions [37], [38], [39], [40], [41], [42], [43], [44], and cancer [45], [46], [47], [48], [49], [50], [51], [52], [53], have also been linked to lncRNA dysregulation. According to recent studies, lncRNAs could be the crucial component needed in the control and modulation of the growth of mesenchymal stem cells (MSCs) [54], [55], [56], [57]. In this study, we review novel insights into the role of lncRNAs in Treg cell differentiation across a range of pathologies, such as cancer, autoimmune diseases, gynecological diseases, and other immune-related disorders.