The human immune system is a complex network of cells and organs working to protect the body from foreign invaders like bacteria, viruses, and abnormal cells. T cells, a type of white blood cell, are central to this defense, identifying and eliminating threats. While many T cells are well-known for their distinct roles, a unique and less common subset, Double Negative T cells, also contributes to immune responses. These cells possess specialized characteristics that allow them to participate in various aspects of immunity, often differing from their more conventional counterparts.
Defining Double Negative T Cells
Double Negative (DN) T cells are characterized by the absence of two specific co-receptors on their surface: CD4 and CD8. Most conventional T cells express either CD4, defining helper T cells, or CD8, defining cytotoxic T cells. This “double negative” designation describes their lack of both markers.
Despite lacking these co-receptors, DN T cells still possess a T-cell receptor (TCR), allowing them to recognize specific antigens. They can express either the alpha-beta (αβ) or gamma-delta (γδ) chains of the TCR. While they constitute a relatively small percentage of T lymphocytes in peripheral blood, DN T cells are found in various locations throughout the body, including secondary lymphoid organs and non-lymphoid tissues like the kidney, lung, liver, and intestinal epithelium.
The Roles of Double Negative T Cells in Immunity
Double Negative T cells perform a range of functions within the immune system, contributing to both immune regulation and direct cellular defense. Their actions help maintain immune balance and prevent excessive responses that could harm the body’s own tissues.
One significant role of DN T cells is immunoregulation, where they help to suppress or control immune responses. These regulatory DN T cells can prevent the immune system from overreacting, which is important for maintaining immune tolerance and preventing autoimmunity. They achieve this by influencing the activity of other immune cells, such as CD4+ and CD8+ T cells, B cells, and dendritic cells.
DN T cells also demonstrate cytotoxic capabilities, meaning they can directly kill target cells. This function allows them to eliminate virally infected cells or tumor cells, even without the typical CD4 or CD8 co-receptor pathways.
DN T cells also play a part in maintaining immune tolerance, which is the process by which the immune system learns not to attack the body’s own healthy cells and tissues. This involves their capacity to suppress autoreactive T cells that might otherwise target self-antigens, helping to restore balance in the immune system.
Double Negative T Cells and Their Impact on Health
Dysregulation or imbalances in Double Negative T cells can be associated with a variety of health conditions, highlighting their complex involvement in both protective and pathogenic immune processes. Their altered function can contribute to the development or progression of several diseases.
In autoimmune diseases, DN T cell dysfunction can play a role in conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis. An accumulation of DN T cells has been observed in individuals with autoimmune lymphoproliferative syndrome (ALPS). In some autoimmune conditions, expanded DN T cells in inflamed tissues may produce various cytokines, contributing to disease development.
Regarding cancer, DN T cells can have a dual role. They may contribute to anti-tumor immunity by directly killing cancer cells. However, in certain cancer types, DN T cells might also contribute to tumor progression or evasion of the immune system, depending on the specific tumor microenvironment.
DN T cells also have relevance in transplantation, particularly in preventing graft-versus-host disease (GVHD) and promoting transplant tolerance. Studies have shown that infusing allogeneic DN regulatory T cells can prevent GVHD induced by other donor T cells after bone marrow transplantation. This suggests a potential therapeutic application in promoting acceptance of transplanted organs or tissues.
In the context of infections, DN T cells are involved in controlling certain viral or bacterial pathogens. They participate in both innate and adaptive immune responses. For example, in individuals infected with Leishmania, TCRαβ+ DN T cells may contribute to a pro-inflammatory response, while TCRγδ+ DN T cells might act as negative regulators of the immune response.