T Cell
Background
T cells are a subset of white blood cells called lymphocytes, and they play a crucial role in the immune system's defense against pathogens and abnormal cells. They are named "T" cells because they mature in the thymus gland, a small organ located behind the breastbone.
Fig.1 T cell development experiences three key steps: T cell lineage commitment, β-selection, and CD4/CD8 lineage choice. Overview of thymocyte development and regulatory mechanism. (Sun L, et al., 2023)T cells are a diverse group with distinct types and functions. Here are the main types of T cells and their basic functions:
Helper T Cells (Th cells or CD4+ T cells)
Helper T cells are essential for orchestrating and regulating immune responses. They recognize antigens presented by antigen-presenting cells (APCs) such as macrophages and dendritic cells. Once activated, helper T cells produce signaling molecules called cytokines that help activate other immune cells, such as B cells and cytotoxic T cells, to eliminate the invading pathogens. Helper T cells are further classified into different subsets, including Th1, Th2, Th17, and T follicular helper (Tfh) cells, each specialized in promoting specific immune responses.
Cytotoxic T Cells (CTLs or CD8+ T cells)
Cytotoxic T cells are responsible for directly killing infected cells, cancer cells, and cells displaying foreign antigens. They recognize antigens presented on the surface of infected or abnormal cells through their T cell receptors (TCRs). Once activated, cytotoxic T cells release toxic substances, such as perforin and granzymes, or trigger apoptosis (programmed cell death) in the target cells. This process helps eliminate the source of infection or control the growth of abnormal cells.
Regulatory T Cells (Tregs)
Regulatory T cells play a critical role in maintaining immune tolerance and preventing excessive immune responses. They help control and regulate the immune system to prevent the immune system from attacking the body's own tissues. Tregs express the transcription factor FoxP3 and suppress the activity of other immune cells, such as effector T cells and APCs, through various mechanisms. This helps maintain immune balance and prevent autoimmune reactions.
Memory T Cells
Memory T cells are long-lived cells that persist after an initial immune response. They are formed as a result of the immune system's encounter with specific pathogens or antigens. Memory T cells "remember" the antigen they previously encountered and mount a rapid and robust immune response upon re-exposure to that antigen. This memory response allows for a more effective and efficient elimination of the pathogen.
Gamma delta T Cells
Gamma delta (γδ) T cells are a unique subset of T cells that possess a distinct T cell receptor (TCR) composed of gamma and delta chains instead of the more common alpha and beta chains. They represent a small fraction of T cells in the peripheral blood and various tissues. Gamma delta T cells have diverse functions, including early immune defense, tissue repair, and regulation of immune responses. They can recognize a broad range of antigens, including stress-induced molecules and non-peptide antigens, without the need for major histocompatibility complex (MHC) presentation.
These various types of T cells work together to provide a coordinated immune response. They interact with other immune cells, such as B cells, dendritic cells, and macrophages, to mount effective immune responses against infections, eliminate abnormal cells, and maintain immune homeostasis.
T cells play a crucial role in adaptive immunity, which is characterized by the ability to recognize specific antigens and generate a targeted immune response. Understanding the functions and interactions of T cells is essential for advancing knowledge of the immune system and developing strategies to combat infections, autoimmune diseases, and cancer.
Recent Advances in T-cell Research
CAR-T Cell Therapy
CAR-T cell therapy has shown remarkable success in treating certain hematological malignancies. Recent advances have focused on optimizing CAR design, improving manufacturing processes, and expanding its application to solid tumors. Additionally, efforts have been made to mitigate side effects, such as cytokine release syndrome and neurotoxicity, associated with CAR-T therapy.
T-Cell Engineering
Researchers are exploring various strategies to enhance the function and specificity of T cells. This includes gene editing techniques like CRISPR-Cas9, which allow precise modification of T cells to improve their tumor-targeting ability and persistence. TCR (T-cell receptor) engineering and the development of universal "off-the-shelf" T cells are also areas of active investigation.
Neoantigen Vaccines
Neoantigens are unique antigens expressed by tumor cells. Recent research has focused on developing personalized neoantigen vaccines that stimulate T-cell responses against specific tumor mutations. These vaccines aim to generate potent and durable anti-tumor immune responses, offering a promising avenue for cancer immunotherapy.
T-Cell Exhaustion
T-cell exhaustion is a state of dysfunction observed in chronic viral infections and cancer. Recent studies have deepened our understanding of the molecular and epigenetic mechanisms underlying T-cell exhaustion. This knowledge informs the development of strategies to reverse or prevent exhaustion, such as checkpoint inhibitors and metabolic interventions.
Immunotherapy Combinations
Combination immunotherapies involving T-cell-targeting agents, such as immune checkpoint inhibitors, have gained significant attention. Researchers are exploring synergistic interactions between different immunotherapies to enhance treatment responses. This includes combining CAR-T therapy with checkpoint inhibitors or other modalities to improve efficacy and overcome resistance.
Single-Cell Analysis
Single-cell analysis techniques, such as single-cell RNA sequencing and mass cytometry, have revolutionized our understanding of T-cell heterogeneity and functional states. These technologies enable the characterization of individual T cells and the identification of rare subsets with distinct functions. Single-cell analysis provides insights into T-cell differentiation, activation, and responses to therapies.
CRISPR Technology
CRISPR-Cas9 gene editing has emerged as a powerful tool in T-cell research. It allows precise modification of T-cell genomes, enabling the introduction or deletion of specific genes. Researchers are using CRISPR technology to enhance T-cell efficacy, improve tumor targeting, and engineer resistance to inhibitory signals.
The Development Trend and Future Research Direction in the Field of T Cells
T Cell Engineering and Synthetic Biology
Researchers are likely to continue advancing T cell engineering techniques, such as CAR-T cell therapy, to improve efficacy, safety, and applicability. This may involve optimizing CAR design, exploring new target antigens, and developing strategies to overcome tumor immune evasion. Additionally, the field of synthetic biology may offer opportunities to engineer T cells with enhanced functionalities or novel abilities.
Immune Memory and Long-Term Protection
Understanding the mechanisms underlying T cell memory formation, maintenance, and long-term protection will remain a key area of research. Unraveling the factors that contribute to the generation of durable immune memory and designing interventions to enhance memory T cell responses could have profound implications for vaccine development, immunotherapy, and infectious disease control.
T Cell Exhaustion and Dysfunction
Investigating the mechanisms underlying T cell exhaustion and dysfunction in chronic infections, cancer, and autoimmune diseases will continue to be a focal point. Researchers will likely explore strategies to reverse or prevent T cell exhaustion, such as targeting inhibitory receptors or metabolic pathways, to restore T cell function and improve immune responses.
T Cell Metabolism and Immunometabolism
The field of immunometabolism will likely see further exploration of the intricate relationship between T cell metabolism and immune functions. Researchers may investigate how metabolic pathways, nutrient availability, and environmental cues modulate T cell responses. Targeting metabolic pathways to manipulate T cell function and enhance immunotherapy outcomes could be a promising avenue for future research.
Single-Cell Analysis and Systems Immunology
Advancements in single-cell analysis techniques will continue to revolutionize our understanding of T cell heterogeneity, differentiation, and functional states. Researchers will likely employ multi-omics approaches, combined with computational modeling, to decipher complex T cell regulatory networks and identify novel therapeutic targets. Systems immunology approaches will contribute to a more comprehensive understanding of T cell biology and immune responses.
T Cell-Based Vaccines and Immunotherapies
Developing T cell-based vaccines and immunotherapies will remain an active area of research. This includes the design of vaccines that elicit robust T cell responses against infectious diseases, cancer, or emerging pathogens. Additionally, combining T cell-based immunotherapies with other treatment modalities, such as checkpoint inhibitors or targeted therapies, may provide synergistic effects for improved clinical outcomes.
Fig.3 T cells dysregulation in critical illnesses. T cell alterations include lymphopenia with polarization of Th cells towards Th2, increase of Th17 cells, increase of Tregs and reduction of innate T cells (MAIT cells and γδT cells). (Luperto M, et al., 2022)Case Study
Case 1: Roberts A, Bentley L, Tang T, et al. Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation. Sci Rep. 2021;11(1):4030.
In the tumor microenvironment, presumed as a result of chronic antigen exposure, T cells can show a dysfunctional or 'exhausted' phenotype. The authors wanted to assess the effect of pembrolizumab on cytokine production by cells that had previously been chronically activated. The authors first stimulated CD4+ T cells with PHA for 14 days, which increased the percentage of cells expressing PD-1, LAG-3, CTLA-4, and TIM-3 and the MFI; the number of TIGIT-positive cells did not change significantly in this model.
Fig.1 Exhausted CD4+ T cell phenotype.Case 2: Shive CL, Freeman ML, Younes SA, et al. Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-β Levels in Treated HIV+ Immune Non-responders. Front Immunol. 2021;12:638010.
The aim of this study was to investigate T-cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. The authors measured markers of T-cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) in HIV+ participants grouped by CD4 T-cell counts who were treated as immune unresponsive persons (INR). Immune parameters were also measured in HIV-uninfected age-distributed matched controls. Associations between T-cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank statistics. The results showed that the proportion of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) was elevated in HIV+ participants.
Thawed PBMCs were stained with live/dead stain, for CD4 and CD8 T cell subsets, and for CD45RA and CD27 to determine maturation subsets (naïve = CD45RA+CD27+; central memory CM = CD45RA-CD27+; effector memory EM = CD45RA-CD27-; terminal effector memory TEM = CD45RA+CD27-). Live gated CD3+CD4+ T cells were assessed for the proportion of CD57 (A), PD-1 (B), TIGIT (C), and KLRG-1 (D) within each maturation subset.
Fig.2 Proportions of T cell exhaustion and senescence markers on CD8 naïve, CM, EM, and TEM T cell subsets.References
- Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther. 2023;8(1):235.
- Kumar BV, Connors TJ, Farber DL. Human T Cell Development, Localization, and Function throughout Life. Immunity. 2018;48(2):202-213.
- Luperto M, Zafrani L. T cell dysregulation in inflammatory diseases in ICU. Intensive Care Med Exp. 2022;10(1):43.
