Regulation gone awry? Elevated levels of regulatory T cells linked To disease progression
Richard Jefferys, TAG
Over the past decade it has become accepted that some T cells play a role in dampening down immune responses. These cells are dubbed regulatory T cells or Treg for short. In lab studies, Treg have been shown to suppress the activation of other T cells, and there is considerable evidence that this regulatory function is also performed in vivo.
One problem, however, is that there are no definitive markers for Tregs. Initially, expression of a molecule called CD25 was used to define Treg, but CD25 can also be upregulated by other activated T cells. More recently, a transcription factor, Foxp3, has emerged as a more specific marker for Treg. Although several studies have explored the role of Treg in HIV infection, results have been inconsistent and hard to interpret because approaches to define the cells have varied. A new study in the journal AIDS Research & Human Retroviruses uses the combination of CD25 and Foxp3 to explore whether Treg levels differ in individuals with varying rates of disease progression.
Weiwei Cao and colleagues from UCLA employed a case-control approach to compare twenty fast progressors from the Multicenter AIDS Cohort Study (MACS) to forty matched slow progressors and nine uninfected individuals. Fast progression was defined as an AIDS diagnosis within 4 years after enrolment into MACS, whereas slow progressors were categorized based on the absence for an AIDS diagnosis for at least 8 years after entry into the cohort. Treg constituted 4.6% of CD4 T cells in uninfected study participants and this proportion was only slightly increased to 5.6% in slow progressors. Among fast progressors, however, the proportion of Treg was significantly higher at 11.3%. Further analysis showed that Treg levels correlated with CD4 T cell activation; the proportion of CD4 T cells expressing the activation marker CD38 was 1.5% in uninfected individuals, 7.2% in slow progressors and 16.3% in fast progressors.
In the discussion section of the paper, Cao and colleagues suggest that these two phenomena may be linked, because other studies have shown that T cell activation can lead to the generation of Foxp3-expressing Treg from resting T cells that previously did not express the marker. Therefore it is possible that the persistently elevated levels of T cell activation in HIV infection leads to the observed accumulation of Tregs. Some researchers have suggested that immune activation in HIV infection is caused by a lack of Treg, but Cao and colleagues note that their data appears incompatible with this possibility. Rather, their data argues that Treg either have a negative effect perhaps by interfering with HIV-specific immune responses, as some prior studies have posited or alternatively the relative expansion of Tregs is just a by-product of immune activation which has no specifific role in HIV disease progression.
TAG Basic Science Weblog. (10 Mar 2009)
Michael Palm Basic Science, Vaccines & Prevention Project Weblog: Regulation Gone Awry? Elevated Levels of Regulatory T Cells Linked To Disease Progression
Cao W et al. Regulatory T Cell Expansion and Immune Activation during Untreated HIV Type 1 Infection Are Associated with Disease Progression AIDS Research and Human Retroviruses. February 2009, 25(2): 183-191. doi:10.1089/aid.2008.0140. Free access to full text PDF.