T cells are specialized white blood cells that form a central part of the body’s adaptive immune system. Their role involves recognizing and eliminating specific threats, such as virus-infected cells or cancer cells. T cell expansion refers to the process by which these cells rapidly increase in number in response to a perceived danger. This multiplication ensures enough specialized T cells are available to combat and clear a particular pathogen or abnormal cell.
How T Cells Multiply Naturally
The natural multiplication of T cells within the body begins when a naive T cell encounters its specific antigen. This antigen is presented by specialized cells called antigen-presenting cells (APCs) on major histocompatibility complex (MHC) molecules. For CD4+ T cells, antigens are presented on MHC class II molecules, while for CD8+ T cells, they are presented on MHC class I molecules. This initial recognition, known as signal one, involves the T cell receptor (TCR) binding to the antigen-MHC complex.
For full activation and subsequent expansion, a second signal, known as co-stimulation, is required. This involves the CD28 protein on the T cell binding to B7 proteins on the APC. Without this co-stimulatory signal, T cells may become unresponsive rather than activating and proliferating. The binding of CD28 enhances the production of interleukin-2 (IL-2), a cytokine that acts as a growth factor for T cells.
IL-2 then stimulates the activated T cells to undergo rapid proliferation, leading to a large population of T cells specific to the encountered antigen. These newly formed T cells also differentiate into various effector subsets, such as cytotoxic T lymphocytes (CD8+ T cells) that directly kill infected cells, or helper T cells (CD4+ T cells) that coordinate other immune responses.
Expanding T Cells Outside the Body: Why and How
Expanding T cells outside the body is undertaken to generate large quantities of specific T cells for therapeutic applications. The body’s natural immune response may not produce enough T cells quickly or specifically enough to combat certain severe conditions, such as advanced cancers or chronic infections. This expansion allows scientists and clinicians to control the T cell environment and generate vast numbers of highly specialized cells for reinfusion into a patient.
T cells for ex vivo expansion are obtained from a patient’s peripheral blood. Once collected, these T cells need to be activated to induce proliferation. One common method involves using magnetic beads coated with antibodies against CD3 and CD28. The anti-CD3 antibody mimics the signal received when a T cell receptor binds to an antigen, while the anti-CD28 antibody provides the necessary co-stimulatory signal. These beads effectively act as artificial antigen-presenting cells, providing the two primary signals for T cell activation.
In addition to activation signals, T cell proliferation and survival during ex vivo expansion are reliant on specific growth factors, known as cytokines. Interleukin-2 (IL-2) is a widely used cytokine that promotes T cell proliferation, activation, and survival. Other cytokines, such as interleukin-7 (IL-7) and interleukin-15 (IL-15), are also frequently used, sometimes in combination with IL-2, to support robust expansion and influence the resulting T cell phenotype.
Interleukin-21 (IL-21) is another cytokine that can be utilized to promote T cell proliferation and enhance their effector functions. The specific combination and concentration of cytokines used can significantly impact the expansion rate and the characteristics of the expanded T cell population. For instance, a combination of IL-7 and IL-15 with anti-CD3/CD28 stimulation can lead to substantial expansion while preserving antigen specificity. These cells are cultured in specialized, sterile media within incubators that maintain optimal temperature and carbon dioxide levels to support cell growth.
Medical Uses for Expanded T Cells
Expanded T cells have become an important tool in various medical treatments, particularly in the field of immunotherapy. One prominent application is in cancer therapy, specifically Chimeric Antigen Receptor (CAR) T-cell therapy and T-cell Receptor (TCR) T-cell therapy. In CAR T-cell therapy, a patient’s T cells are genetically engineered to express a CAR, a synthetic receptor that allows them to recognize and bind to specific proteins found on the surface of cancer cells. Once infused back into the patient, these modified CAR T cells proliferate and actively seek out and destroy tumor cells, primarily used for blood cancers like leukemia and lymphoma.
TCR T-cell therapy differs in its targeting mechanism. These T cells are modified to express specific T cell receptors that recognize intracellular tumor antigens presented on the cell surface via HLA molecules. This approach shows promise for treating solid tumors, such as lung cancer or melanoma, where CAR T cells may be less effective due to their target recognition. Both CAR T and TCR T cells destroy target cells by releasing cytotoxic molecules.
Beyond cancer, expanded T cells are also being explored for treating persistent infectious diseases. T cell therapies have demonstrated efficacy against chronic viral infections. These therapies involve isolating and expanding virus-specific T cells, which are then reinfused into patients to bolster their immune response against the pathogen. The aim is to enhance the patient’s ability to clear the infection, especially in individuals with weakened immune systems.
Expanded T cells also hold potential for modulating immune responses in autoimmune diseases. Regulatory T cells (Tregs), a specific subset of T cells, play a role in maintaining immune tolerance and preventing excessive immune reactions. By expanding and reinfusing Tregs, researchers are investigating their ability to suppress overactive immune responses that cause autoimmune conditions. This approach seeks to restore balance to the immune system and alleviate disease symptoms.
Traits of Successfully Expanded T Cells
Successfully expanded T cell populations possess several characteristics that determine their therapeutic effectiveness. Achieving a sufficient quantity of cells is important, as clinical applications often require large numbers of T cells to have a meaningful impact within the body.
Beyond sheer numbers, the purity and viability of the expanded T cell product are also important. Purity refers to the percentage of the desired T cell subset within the total cell population, while viability indicates the proportion of live, healthy cells. A high percentage of live, functional T cells is preferred for optimal therapeutic outcomes.
The phenotype of the expanded T cells, which refers to their observable characteristics and surface markers, is another important quality. Different T cell subsets have varying capacities for persistence, proliferation, and immediate effector function. Avoiding terminal differentiation or exhaustion, where T cells lose their ability to function effectively, is also a consideration.
Finally, the functionality of the expanded T cells is assessed to confirm their ability to perform their intended immune roles. This includes evaluating their capacity to kill target cells, produce relevant cytokines, or regulate immune responses depending on their specific therapeutic purpose. Demonstrating these functions provides confidence that the expanded cells will be effective once administered to a patient. Safety considerations, such as ensuring the absence of contaminants and preventing unintended immune reactions, are also a standard part of quality control for these cell therapies.