Depletion of T-lymphocytes
Marina Dukhinova, "Elements"
This micrograph shows how T-lymphocytes (yellow) attack a cancer cell (pink), which they recognize by antigens on its surface. Photos from the website dailymail.co.uk , the photo was taken using a scanning electron microscope, magnification: 2600×.
The purpose of T-lymphocytes is to prevent metastasis and destroy the tumor. The goal of cancer cells is to survive, for which they need to suppress the work of T–lymphocytes, literally bringing them to exhaustion (see T cell exhaustion). Depleted T-lymphocytes are no longer able to protect the body from cancer, infection or inflammation.
T-cells, or T-lymphocytes, are an important component of the system of innate and adaptive immunity (see The analog of the chemical synapse found in the human immune system, "Elements", 03.08.2018). They are involved in the body's fight against infectious diseases and cancer. Two main populations of T-lymphocytes are known: T-helpers identify a potentially dangerous target and present its antigen on their surface; after that, the pathogen becomes a target for T-killers – cell killers that destroy the body's enemies.
In the early stages of activation, T-lymphocytes work at full capacity: T-helpers recognize their enemies and activate B-lymphocytes and T-killers, which successfully join the fight. Over time, however, the depletion of T-lymphocytes occurs and the fight weakens: T-helpers stop recognizing pathogens and attracting other cells to fight them, and T-killers lose their cytotoxic potential.
Why are T-lymphocytes depleted? One of the reasons is the so–called desensitization. Imagine that you hear an incessant noise outside the window and can't do anything about it. At first he will annoy you, and then you will stop paying attention to him – this is desensitization. Similarly, T-helpers, constantly surrounded by cancer cells or pathogens, ignore enemy signaling molecules, considering them part of a normal, healthy organism. Such T-helpers are no longer able to attract other cells to fight. At the same time, the activity of lymphocytes is not disturbed, but the threshold level of molecules necessary for their activation increases.
Another mechanism is changes in the cellular activity of T–helpers and T-killers. They decrease the reserves and production of active substances – the antigen-presenting complex in T-helpers and molecules necessary to fight pathogens, in T-killers: interleukin-2 cytokines, gamma interferon, tumor necrosis factor. Molecular cascades of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) are triggered, which suppress the activity of T-lymphocytes and lead to their death. Changes in the cellular activity of T-lymphocytes occur due to the fact that: a) with a chronic disease, they are constantly in an activated state, without rest and the ability to restore the stock of active molecules; b) their work is actively suppressed by cancer cells (see figure below).
The cancer cell expresses CD80 and PD-L1 protein molecules that interact with CTLA-4 and PD-1 receptors and trigger molecular cascades of dysfunction and cell death in T-lymphocytes. Drawing from the website medicalxpress.com , with changes.
In general, the phenomenon of depletion is in many ways similar to premature cellular aging: both senescent and depleted T-lymphocytes do not express CD28 protein, which is why they lose their ability to activate after interacting with an antigen and are unable to synthesize cytokines to fight infections or cancer and attract other immune cells. T-lymphocytes, exhausted by the prolonged (and unsuccessful) struggle and insidious attacks of cancer cells, gradually cease to resist... Depletion of T-lymphocytes is one of the main reasons for the inability of the body to fight numerous forms of cancer and chronic infections, such as hepatitis B virus and C or human immunodeficiency (HIV). And over time, the dysfunction only progresses: depleted T-lymphocytes less and less successfully attract new immune cells to the foci of the disease, and the number of newly formed cells is insufficient for the patient.
However, there is also good news: the depletion of T-lymphocytes is reversible, and modern methods of treating cancer and chronic infections are aimed at reviving them. To do this, a variety of inhibitors blocking CTLA-4 and PD-1 cascades, as well as immunostimulants are used. Such inhibitors have passed successful clinical trials in the treatment of melanoma, Hodgkin's lymphoma, non-small cell lung carcinoma and other cancers.
Interestingly, sometimes the depletion of T-lymphocytes, on the contrary, turns out to be favorable for the patient. Any organ transplantation procedure, such as a donor kidney or heart transplant, triggers an immune response and activation of the recipient's T-lymphocytes. As soon as they are depleted, the risk of transplant rejection decreases and the patient enters the recovery phase. Also, the phenomenon of exhaustion plays a positive role in autoimmune and inflammatory diseases. Research on the role of depleted T-lymphocytes and their therapeutic use is actively developing, and we are waiting for further scientific and medical breakthroughs in this area.
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