Cell-Mediated Immunity: T Cells and Cytotoxic Action

Cell-mediated immunity is the arm of adaptive immunity carried out by T lymphocytes (T cells), which coordinate the immune response (helper T cells) and destroy infected or abnormal body cells directly (cytotoxic T cells). In brief: T cells mature in the thymus and recognize antigens only when they are displayed on the surface of body cells by special proteins. Helper T cells (CD4) release chemical signals that activate B cells and cytotoxic T cells, while cytotoxic T cells (CD8) kill virus-infected cells and tumor cells. HIV infects and destroys helper T cells.

Antibodies cannot reach pathogens hiding inside cells, such as viruses, so T cells are needed. This guide explains lymphocytes, how antigens are presented, the roles of helper and cytotoxic T cells, how a virus-infected cell is killed, compares T cells and B cells, works through an HIV example and corrects common mistakes.

What are lymphocytes?

Lymphocytes are white blood cells that make up about 20 to 40 percent of the total. They are produced in the bone marrow. The two main types are B cells, which mature in the bone marrow, and T cells, which migrate to the thymus, a gland behind the breastbone, to mature. In the thymus, T cells that react against the body’s own molecules are eliminated, which gives self-tolerance. The thymus is largest in children and shrinks with age. Lymphocytes travel through the blood and lymph and gather in lymph nodes, the spleen and tonsils.

How are antigens presented to T cells?

Unlike B cells, T cells cannot bind free antigens. They recognize fragments of antigens (peptides) that are displayed on the surface of a cell by proteins called MHC molecules (major histocompatibility complex, also called HLA in humans).

• MHC class I is present on almost all body cells. A cell displays fragments of proteins made inside it, including viral proteins if it is infected. These are recognized by cytotoxic T cells (CD8).
• MHC class II is found on antigen-presenting cells (macrophages, dendritic cells and B cells), which display fragments of pathogens that they have engulfed. These are recognized by helper T cells (CD4).

Each T cell has a receptor (TCR) specific for one antigen-MHC combination. MHC molecules differ greatly between people, which is the reason why transplanted organs are rejected unless they are matched closely, and why donors must be matched with recipients.

What do helper T cells do?

Helper T cells (T_H cells) are the coordinators of the immune system. When a helper T cell with a matching receptor recognizes an antigen on an antigen-presenting cell, it is activated, divides and releases cytokines, signaling proteins. These have several effects:

• They activate B cells, stimulating them to divide and become plasma cells.
• They activate cytotoxic T cells, making them divide.
• They stimulate macrophages to be more effective killers.

Without helper T cells, both the humoral and cell-mediated responses are weak, which is the reason that the loss of these cells in HIV infection leads to AIDS.

What do cytotoxic T cells do?

Cytotoxic T cells (CD8, also called killer T cells) destroy cells that are infected with viruses or other intracellular pathogens, tumor cells and transplanted cells. The steps are:

1. The TCR of a cytotoxic T cell binds to an antigen-MHC I complex on an infected cell. The T cell needs signals from helper T cells to be fully activated and to divide into a clone.
2. The cytotoxic T cell releases the protein perforin, which makes pores in the membrane of the target cell, and granzymes, enzymes that enter through the pores and trigger the cell’s programmed death (apoptosis). Another route involves surface proteins (Fas ligand).
3. The infected cell dies and the virus inside it cannot reproduce. The T cell detaches and can kill other cells, one after another.

Natural killer (NK) cells of the innate system also kill infected cells and tumor cells, but unlike cytotoxic T cells they do not need a specific antigen. They attack cells that have lost their MHC I molecules, which some viruses and cancers do to avoid T cells.

B cells and T cells compared

Do T cells form memory?

Yes. After the infection ends, most activated T cells die, but some remain as memory T cells (helper and cytotoxic). They respond faster and more strongly to a second exposure to the same antigen. Memory T cells can persist for decades. Regulatory T cells are another type, which suppress the immune response and prevent excessive reactions and autoimmunity.

Worked example: a virus infects a cell

Follow the response to an influenza virus that infects cells in the lining of the airway.

1. Virus enters an epithelial cell and starts to replicate. The cell displays fragments of viral proteins on MHC I. Interferon released by the cell warns neighbors.
2. A dendritic cell takes up virus particles, travels to a lymph node and displays viral peptides on MHC II to helper T cells. The helper T cell with the matching receptor is activated and divides.
3. The helper T cells release cytokines and activate cytotoxic T cells with receptors for the viral peptide on MHC I, and B cells that bind viral proteins.
4. Cytotoxic T cells multiply and migrate to the lungs, where they find infected cells displaying the peptide and kill them with perforin and granzymes. B cells produce antibodies that neutralize free virus.
5. After about one to two weeks, the infection is cleared. Memory T and B cells remain.

For HIV, the problem is that the virus enters helper T cells through the CD4 receptor and destroys them. A healthy adult has roughly 500 to 1 500 CD4 T cells per microliter of blood. In untreated HIV infection the count gradually falls, and below 200 per microliter the diagnosis of AIDS is made, since the body can no longer fight infections that it would normally control. Antiretroviral therapy suppresses the virus, and the CD4 count can recover to near-normal levels, so people with HIV can have a normal life expectancy.

How were T cells discovered?

Jacques Miller discovered in the early 1960s that the thymus is needed for immune function, by removing it from newborn mice. The distinction between B cells and T cells was made in the 1960s and 1970s. Rolf Zinkernagel and Peter Doherty found in 1974 that T cells recognize antigens together with MHC molecules, which was recognized by the 1996 Nobel Prize in Physiology or Medicine. HIV’s attack on CD4 cells was described in the early 1980s. Cancer immunotherapy that uses T cells, such as checkpoint inhibitors, was recognized by the 2018 Nobel Prize awarded to James Allison and Tasuku Honjo.

Which mistakes are common?

Mistake 1: Saying that T cells make antibodies

B cells (plasma cells) make antibodies. T cells coordinate or kill.

Mistake 2: Thinking T cells recognize free antigens

They need antigens displayed on MHC molecules.

Mistake 3: Mixing up the helper and cytotoxic functions

Helper T cells signal. Cytotoxic T cells kill.

Mistake 4: Saying that HIV kills the patient directly

It destroys helper T cells, so the body loses its ability to fight other infections and some cancers.