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Memory Inflation as a Doorway to Sustained Immune Response

Cytomegalovirus (“CMV”) is a common virus that infects one in every two people in many developed countries. Most CMV infections are “silent,” meaning most people who are infected with CMV exhibit no signs or symptoms because the infection is effectively controlled by the immune system.

Long-term control of CMV requires an intricate, multi-pronged immune response. One hallmark of CMV infection is the maintenance of a large population of CMV-specific T cells that control the disease – a phenomenon termed “memory inflation”. In a recent Nature Review Immunology article, Paul Klenerman and Annette Oxenius summarize the current understanding of the mechanisms of these T cell responses to CMV, and demonstrate the potential of harnessing memory inflation to power vaccine design.

When a virus infects a human host, it sequesters itself into a cell. This defense mechanism allows the virus to go unseen by the part of the innate immune system that attacks pathogens that sit outside of cells. The immune system, however, is equipped to detect these hidden pathogens. Proteins called major histocompatibility complexes sit on the membranes of cells and present protein fragments from the inside of the cell to the surrounding environment. When the proteins from pathogens are presented, circulating CD8+ cytotoxic T cells react and mount an attack on the cells they recognize as infected. These CD8+ T cells (also known as “killer T cells”) destroy infected host cells to halt the spread of the virus.

Because CMV is a chronic infection (the virus often persists at low levels in individuals for their entire lifespan), the persistent presence of a virus in the circulation can have a dramatic effect on CD8+ T cell differentiation and survival. In some chronic viral infections like HIV or hepatitis C, sustained stimulation leads to virus-specific T cell “exhaustion” and the host progressively loses T cells and, therefore, the ability to fight back against the pathogen.

However, unlike many other chronic infections, after exposure to CMV, the CD8+ T cell population specific to CMV exhibits an atypical pattern of sustained expansion or memory inflation. These T cells continue to produce substances to fight the CMV virus and prevent further infection.

As seen in other immune responses to viruses, CD8+ T cells exhibit what is considered a “classical memory response” to initial CMV infection. The killer T cell population and activity rise throughout the body. In the blood and secondary lymphoid organs (the lymph nodes) a subset of CD8+ T cells, called the central memory (“TCM”) cells, expand. The spleen and peripheral tissues are dominated by effector memory (“TEM”) cells.

In other diseases, after the initial infection, the number of TEM cells in the blood falls while the TCM levels are maintained. However, unique to the CMV response, after this acute phase of infection, the effector memory cell subset undergoes expansion and persists even after the presence of CMV declines.

In healthy individuals, memory inflation has key features that helps control the spread of CMV and prevent illness, specifically:

  • CMV-specific killer T cells do not experience exhaustion and constitute a major proportion of the host’s T cells: Anti-CMV TEM cells segregate at high frequency in the peripheral blood and non-lymphoid tissue (such as the liver and the lungs) and are not subject to T cell “exhaustion” and subsequent apoptosis. These expanded CMV-specific TEM populations regularly constitute 5% to 10% of total CD8+ T cell populations in the blood of latent CMV carriers but can account for as much as 30% of total CD8+ T cells. Researchers hypothesize that this ability may be due in part to the cells reverting to a more “naïve” state, which promotes cell survival.
  • Anti-CMV TEM cells continue to accumulate in the host during his or her lifespan: In typical viral responses, maintaining virus-specific T cell populations is a function of persistent antigen stimulation and cell cycling. Researchers hypothesize that during latent CMV infection, the virus is sporadically reactivated at low levels, causing CMV antigens to be presented to adaptive immune cells in relatively small amounts. This would explain the appearance of new CMV-specific TEM cells in the host.
  • Memory inflation helps to prevent symptomatic reactivation: Overt CMV reactivation is observed only during immunosuppression, for instance after transplants or in patients with AIDS. While research is still being done to better understand if increasing size of anti-CMV killer T-cells populations is correlated to increases in immune protection, it is known that the expanded CD8+ T cell populations do indeed play a protective role.

Researchers are still exploring the causes of the sustained T cell response in hosts. Likely contributors appear to be a combination of genetic factors, immune system CMV processing, and peptide affinity for major histocompatibility complexes.

As CMV infection elicits large T cell responses that accumulate in peripheral tissues, maintain effector functions, and persist longer than typical CD8+ TEM cells, researchers believe these responses could be harnessed in the setting of a vaccine. Memory inflation may also make CMV an attractive vehicle for immunotherapy.

Cancer Cell
Killer T Cell
Killer T Cell
Killer T Cell

A high-resolution image of a group of killer T cells surrounding a cancer cell. Credit: National Institutes of Health