The complexity of intestinal homeostasis results from the ability of the intestinal epithelium to absorb nutrients, harbor multiple external and internal antigens, and accommodate diverse immune cells. Intestinal intraepithelial lymphocytes (IELs) are a unique cell population embedded within the intestinal epithelial layer, contributing to the formation of the mucosal epithelial barrier and serving as a first-line defense against microbial invasion. TCRαβ⁺ CD4^- CD8αα⁺ CD8αβ^- and TCRγδ⁺ CD4^- CD8αα⁺ CD8αβ^- IELs are the two predominant subsets of natural IELs. These cells play an essential role in various intestinal diseases, such as infections and inflammatory diseases, and act as immune regulators in the gut. However, their developmental and functional patterns are extremely distinct, and the mechanisms underlying their development and migration to the intestine are not fully understood. One example is that Bcl-2 promotes the survival of thymic precursors of IELs. Mature TCRαβ⁺ CD4^- CD8αα⁺ CD8αβ^- IELs seem to be involved in immune regulation, while TCRγδ⁺ CD4^- CD8αα⁺ CD8αβ^- IELs might be involved in immune surveillance by promoting homeostasis of host microbiota, protecting and restoring the integrity of mucosal epithelium, inhibiting microbiota invasion, and limiting excessive inflammation. In this review, we elucidated and organized effectively the functions and development of these cells to guide future studies in this field. We also discussed key scientific questions that need to be addressed in this area.

As an important form of posttranslational modification, protein ubiquitination regulates a wide variety of biological processes, including different aspects of T cell development and differentiation. During T cell development, thymic seeding progenitor cells (TSPs) in the thymus undergo multistep maturation programs and checkpoints, which are critical to build a functional and tolerant immune system. Currently, a tremendous amount of research has focused on the transcriptional regulation of thymocyte development. However, in the past few years, compelling evidence has revealed that the ubiquitination system also plays a crucial role in the regulation of thymocyte developmental programs. In this review, we summarize recent findings on the molecular mechanisms and cellular pathways that regulate thymocyte ubiquitination and discuss the roles of E3 ligases and deubiquitinating enzymes (DUBs) involved in these processes. Understanding how T cell development is regulated by ubiquitination and deubiquitination will not only enhance our understanding of cell fate determination via gene regulatory networks but also provide potential novel therapeutic strategies for treating autoimmune diseases and cancer.

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

T-lymphocytes play crucial roles for maintaining immune homeostasis by fighting against various pathogenic microorganisms and establishing self-antigen tolerance. They will go through several stages and checkpoints in the thymus from progenitors to mature T cells, from CD4^-CD8^- double negative (DN) cells to CD4⁺CD8⁺ double positive (DP) cells, finally become CD4⁺ or CD8⁺ single positive (SP) cells. The mature SP cells then emigrate out of the thymus and further differentiate into distinct subsets under different environment signals to perform specific functions. Each step is regulated by various transcriptional regulators downstream of T cell receptors (TCRs) that have been extensively studied both in vivo and vitro via multiple mouse models and advanced techniques, such as single cell RNA sequencing (scRNA-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq). This review will summarize the transcriptional regulators participating in the early stage of T cell development reported in the past decade, trying to figure out cascade networks in each process and provide possible research directions in the future.