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What Are T Cells?
T cells are a large family of white blood cells that play a critical role in the body’s adaptive immune response. They are also known as T lymphocytes since they spend most of their life cycle in the body’s lymph tissues. Like all immune cells, T cells are a part of the vast network of immune response mechanisms that defend the body against infection, cancer, allergens, and other foreign invaders.
What Do T Cells Do?
The role of T cells varies greatly by their type. In general, the primary function of T cells is to become activated when another immune cell presents an antigen from a specific pathogen, toxin, cancer, or other foreign substance.
Once activated, T cells undergo clonal expansion, replicating to increase their numbers in the body. They also gain effector functions, releasing signaling molecules to modulate the adaptive immune response and target the foreign cells via recognition of the antigen previously presented to them. In addition, a small portion of T cells differentiate into memory cells that will help mitigate reinfection, should it occur.
Where Do T Cells Originate?
All immune system cells, including T cells, originate from blood stem cells produced in the bone marrow. Growth factor signaling molecules secreted by cells throughout the body determine how the maturation of these stem cells initially proceeds through their immune cell lineage.
Certain growth factors cause the T cell precursors to transit from the bone marrow to the thymus, a small glandular organ on the neck. Here they undergo thymus-dependent T cell differentiation to express T cell receptors (TCR) on their surface, eventually creating mature, but naive, immune T cells. These naive T cells reside in the body’s lymphatic system tissues until activated.
T Cell Activation
T cell activation occurs when another cell presents an antigen or specific peptide sequence to the T cell via protein complexes on its membrane. For most activation events, the antigen-presenting cell (APC) uses a functional group of membrane proteins called a major histocompatibility complex (MHC) to present the antigen to T cell receptors (TCRs) on the surface of the T cell.
If the T cell’s TCR binds to an antigen-presenting MHC on another cell, the T cell may activate. This presentation step is necessary because TCRs cannot bind antigens directly. For naive T cells in the lymph tissues, this initial activation presentation is thought to only occur with a particular antigen-presenting cell (APC) called a dendritic cell. Once activated, a naive T cell acquires a T cell phenotype determined by the upregulation of CD (cluster of differentiation) antigen surface marker expression.
Class I MHC and class II MHC are the two major types of MHC molecules. Most human cells have class I MHC on their surface. However, class II MHC molecules are only found on the surface of B cells, macrophages, dendritic cells, and some select T cells. Certain T cell types only recognize and bind to a particular MHC class.
Types of T Cells
Once activated by the presentation of antigen by APCs, mature T cells initiate effector functions to respond to the infection source and neutralize the threat. Two major types of mature T cells are differentiated by the coreceptors present to assist in stabilizing MHC binding and activation:
- The CD4+ coreceptor is expressed by helper T cells and helps bind to class II MHC. Following activation, CD4+ helper T cells release small signaling molecules called cytokines that further direct and mediate the immune response via cytotoxic T cells, macrophages, and memory B cells.
- The CD8+ coreceptor is expressed by cytotoxic T cells that help bind the class I MHC and can migrate through the walls of blood vessels and non-lymphoid tissues once activated. When the antigen target of a CD8+ cytotoxic T cell is encountered, the T cell may attack and destroy the cells displaying the antigen directly or use cytokine signaling to recruit macrophages and natural killer (NK) cells to neutralize the invader or infection.
One known exception to the T-cell MHC binding-activation rule is natural killer T cells (NKT), which act as a bridge between the innate and adaptive immune systems. Unlike other effector T cells that recognize peptides and antigens presented only by MHC, NKT cells recognize glycolipid antigens presented by CD1d on the surface of antigen-presenting cells.
Like many T cells, the activation and function of CD4+ and CD8+ T cells are often incredibly complex. Both helper and cytotoxic T cells require several secondary signals or coreceptor binding events to become fully activated and execute a certain function.
For example, helper T cells have a co-stimulatory receptor called CD28 that binds proteins CD80 and CD86. This binding signals the T cell to produce various interleukins, a family of cytokines that modulate further growth, differentiation, and activation of other immune cells during the immune response.
While effector T cells promote inflammation, regulatory T cells (Tregs) serve to control it. Tregs help shut down T-cell mediated immune responses toward the end of an immune reaction and suppress defective autoreactive T cells produced during the maturation process in the thymus.
Both actions are critical to the maintenance of immunological tolerance. Tregs function through several mechanisms, including the production of anti-inflammatory cytokines. Some of these, such as interleukin-10 and transforming growth factor beta, inhibit the activity of other immune cells. Alternatively, Tregs can suppress other immune cells by direct binding through the expression of cell surface molecules like CTLA-4 and PD-1.
Dysfunction of regulatory T cells may lead to the affected individual developing autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. It can also prevent adequate anti-antigen responses that hinder tumor response and can lead to sterilized immunity.
Memory T cells are generated throughout the antigen exposure response along a continuum of differentiation. Unlike many other types of differentiated T cells, memory T cells persist in the body long after the intrusion has been cleared.
When re-exposed to the same pathogen, memory T cells rapidly mount a specific immune response, which is often more rapid and effective than the initial response. During this process, some memory T cells will quickly proliferate and differentiate into effector helper and cytotoxic T cells, bypassing the need for dendritic cells to activate naive T cells in the thymus.
Memory T cells can persist in the body for many years or even decades, providing long-term immunity against that specific pathogen. This mechanism is the basis of many successful vaccines that rely on creating memory T cells through exposure to antigens derived from the pathogen but which are not viably infectious themselves.
Recent scientific developments have revealed that the maturity state of T cells plays an important role in their ability to activate and multiply. This ability peaks early at the stem cell memory (TSCM) phase and greatly diminishes by the time a cell reaches the fully mature terminally differentiated effector memory (TEMRA) phase.
Why Are T Cells Important?
Immune T cells are necessary for the proper function of the immune system and, as described above, are involved in a wide range of immune-related processes. Especially vital to the adaptive immune response, T cells drive the recognition and elimination of specific pathogens, both new and previously seen. They modulate the actions of other immune cells, such as B cells, which differentiate into antibody-producing plasma cells. They are even responsible for the development of immune tolerance, which prevents the immune system from attacking the body’s own healthy tissues through the activity of regulatory T cells.
Harnessing T Cells for Immunotherapy
All of these aspects of T cells make them a great candidate for treating various types of cancer and other diseases. The basic principle of T cell based immunotherapy is to harness the human immune system’s ability to target and destroy cancer tumors or other diseased cells.
In some types of adoptive T cell therapy, a patient’s T cells are removed and genetically re-engineered to produce enhanced proteins on their surface. These are called chimeric antigen receptors, or CARs.
These CAR-containing T cells (CAR-T cells) bind more effectively to specific antigens on the surface of cancer cells, are particularly effective in blood cancers (i.e. liquid tumors), and have been approved by the Food and Drug Administration for such applications. Still, the effectiveness of CAR-T therapies can suffer from resistance over time, which may lead to disease recurrence.
To address this issue, Nanotein Technologies has developed a T cell activator that expands clinically potent, long-lasting T cells based on CAR-T technology. Once a patient’s isolated T cells are modified to include specialized CARs that can recognize and attack cancer cells, Nanotein’s TSCM CAR-T Expansion technology activates the CAR-T cells for ex vivo expansion and generates large numbers of stem cell memory (TSCM) T cells.
The NanoSpark STEM-T Soluble T Cell Activator is highly efficient, producing larger quantities of CAR-T cells in less time than our competitors and without the risk of synthetic contaminants.
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