Star TREC: Revealing the Role of the Thymus

Several studies presented at the 7th Conference on Retroviruses and Opportunistic Infections (CROI) looked at the role of the thymus in HIV. The thymus is a small organ located just behind the breastbone that acts as a finishing school for newly made T-cells. Over the past year or two, new technologies have allowed researchers to demolish what a veteran activist has called "the hoariest dogma of human immunology." The dogma in question was a presumption among researchers that the thymus stopped producing new T-cells once a person reached adulthood. In fact, although the production of new T-cells slows down dramatically as we get older, freshly minted T-cells can be found even in people over 90 years of age.

Thymus Function

Before reviewing the conference studies, it's helpful to back up and look at the function of the thymus and how it contributes to the health of the immune system. T-cells are known to be vital to proper immune function, but the subtler distinctions between different types of T-cells and their various functions has only recently become more clear. T-cells belong to different families that can be identified using markers that are present on the cell's surface. The CD4 marker generally defines helper T-cells, which act as conductors of the complex immune system orchestra. T-cells with the CD8 marker work alongside CD4s, and the CD8 family includes cytotoxic T-lymphocytes or CTLs. CTLs have the vital job of killing cells in the body that are infected with viruses or other infectious agents.

T-cells start life in the bone marrow, as cells called progenitors. If the destiny of the progenitor cell is to become a T-cell, it leaves the bone marrow and heads to the thymus. It is here that progenitors become fully fledged T-cells, acquiring the CD4 or CD8 surface marker that helps govern their function. T-cells also develop another vital surface structure in the thymus: the T-cell receptor (TCR for short). The T-cell receptor acts as a docking bay for materials, like pieces of an infectious agent, that will trigger the T-cell to respond. Any piece of foreign material that can trigger an immune response is called an antigen (in the scientific jargon).

T-cell receptors are generated in the thymus by an essentially random shuffling of the T-cell's genetic code. T-cells with many different shaped receptors are made in this way, to ensure that any potential infection can be responded to by at least some T-cells. Due to the random nature of this process, many T-cells will come up with receptors that match your own body tissues. If these T-cells left the thymus they could trigger an immune response against the body, a problem called autoimmunity. The final job of the thymus is to eliminate these potentially dangerous "self-reactive" T-cells. A surprising 95% of new T-cells are eliminated for this very reason. The remaining 5%, equipped with T-cell receptors that will only dock with foreign materials, leave the thymus to go on patrol around the body.

These new T-cells are called "naive" because they have not yet met an infection that matches their receptor. Scientists now have a way of tracking these newly made, naive T-cells. This technology involves tracking T-cells that have only recently left the thymus, or "recent thymic emigrants" (RTEs). These T-cells can be tracked because the generation of the T-cell receptor leaves some redundant genetic code (DNA) in the cell that scientists can now pick up on tests. These waste sections of DNA are called T-cell Receptor Excision Circles or TREC for short. If the naive T-cell meets and responds to an infectious agent, the cell divides and the TREC degrades and disappears. This makes the TREC marker very specific for naive T-cells that have recently left the thymus.

TREC & the Thymus at Retrovirus

As you may have guessed, it's tracking TREC that has allowed scientists to spot newly made naive T-cells in people over 90 years old. While most naive T-cells are indeed produced during childhood, it's now clear that there is a slower, steady production of new naive T-cells throughout adulthood which declines only slowly with age. At CROI, the first ever study looking at the link between production of new naive T-cells and HIV disease progression was presented. The study was conducted by David Ho's team at the Aaron Diamond Center in New York City, and shortly after the conference it appeared in the medical journal The Lancet.

Ho's group found that the number of new naive cells, as measured using TREC, declines as disease progresses. In fact, this decline of TREC was very strongly linked to disease progression, leading the study authors to suggest that TREC measurements may complement T-cell counts and viral load when monitoring HIV infection. The decline in TREC in HIV infection was much more rapid than the age-related decline seen in healthy individuals.

Other studies at CROI looked for explanations for the loss of naive T-cells in HIV infection. Frank Miedema's team at the University of Amsterdam looked for evidence of thymus dysfunction, but found none. What Miedema did find was higher than normal levels of naive T-cell division. In other words, new naive T-cells seemed to be responding to an infectious agent of some sort. Not surprisingly, Miedema revealed in a separate study that the agent responsible is likely to be HIV.

A second conference presentation by David Ho's group provided further evidence that this loss of naive T-cells is important in HIV progression. Ho compared two species of monkey infected by their equivalent to HIV, SIV (simian immunodeficiency virus). One species, sooty mangabeys, does not experience disease from SIV infection. The other species, macaques, develops immune deficiencies similar to AIDS. Ho found that naive T-cell division and TREC levels were normal in the sooty mangabeys, but abnormal in the macaques. Ho concluded, "normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts."

Studies of HAART in both adults and children provided some good news. Viral load suppression was associated with increased TREC levels in adults after 48 weeks of treatment in a combined American/Canadian Study. A Texan study of children on HAART found that those who maintained undetectable viral loads also showed increased TREC levels.

An intriguing study from France looked at the role of naive T-cell production in people with a "discordant response" to HAART treatment. In these individuals, CD4 counts had risen significantly despite a disappointing drop or rapid rebound in viral load. When compared to similar individuals with more modest CD4 increases, the "discordant" responses were associated with higher TREC levels (increased survival of newly made naive T-cells).

A complementary study from Michael Lederman's team at Case Western Reserve looked at the other type of "discordant response" to HAART: good viral load reduction but poor CD4 cell increases. Lederman found that the failure of the thymus to generate new naive T-cells may explain these responses.

It is clear from these studies that the production of new naive T-cells by the thymus is important for maintaining health. The studies also suggest that increasing thymic production of new naive T-cells might be useful therapeutically. It is currently unclear whether it's possible for the thymus to "speed up" production. So far, studies in mice have found it almost impossible to manipulate the thymus in this way. A study at CROI optimistically posited that a cytokine called interleukin-7 (IL-7) might increase thymic output of new naive T-cells. The cytokine (one of the chemical messengers of the immune system) seemed to have this effect in genetically altered mice, although it also caused increased levels of HIV replication.

A late-breaking CROI presentation from Mike McCune and fellow researchers at the Gladstone Institute in San Francisco looked at IL-7 levels in HIV-infected humans. McCune found that IL-7 levels increased as disease progressed and T-cell counts declined. The research team concluded that the body may in fact be trying to boost T-cell production by increasing IL-7 levels as much as possible. Further investigations of the role of IL-7 are planned.

CROI included 20 studies looking at the role of the thymus, demonstrating that this is a growing field. The apparently critical role of the thymus in both disease progression and immune reconstitution will only increase the focus on this formerly under-appreciated organ. Stay tuned.

Richard Jeffreys oversees the Access Project, a national database of AIDS drug assistance programs at the AIDS Treatment Data Network.