In the new issue of the journal Blood, Angélique Biancotto and colleagues from Mike Lederman’s lab at Case Western Reserve University provide a detailed description of the immunological perturbations of the lymph node caused by HIV infection. The researchers found significantly elevated levels of activated CD4 and CD8 T cells in lymph node samples from HIV-infected individuals compared to uninfected controls, consistent with the increasingly well-described role of immune activation in HIV pathogenesis. Activation was assessed by expression of the marker CD38 and 73.3% of the T cells from infected nodes were CD38+ compared to 13.7% in uninfected nodes. A more detailed analysis of CD38 expression on different subsets of CD4 and CD8 T cells showed that levels were elevated on all subsets (naïve, effector memory and central memory CD4 and CD8 T cells). Looking at these subsets also revealed that infected lymph nodes had consistently higher proportions of both CD4 and CD8 effector memory T cells (effector memory T cells are short-lived cells that are generated when T cells are activated; their normal role is to traffic out of the lymph nodes and into the tissues). Consistent with this result, more T cells in infected nodes expressed CD95, a molecule associated with apoptosis (cell death).
Other findings were that the proportions of CD4 T cells was reduced (37.1% vs. 81.7%) in infected lymph nodes while the fraction of CD8 T cells was increased (63.2% vs. 22.6%); the numbers of antigen-presenting cells (called plasmacytoid and myeloid dendritic cells) were also reduced (0.73% vs. 27.1% and 0.46% vs. 8.9%, respectively). Lastly, an analysis of cytokines and chemokines found that IL-1beta, IL-2, IL-10, IL-12 and IL-15 levels were all significantly elevated in infected nodes while concentrations of MIP-1beta, SDF-1beta and IP-10 were significantly diminished.
In discussing the results, the authors suggest that the activation they documented is not the result of specific engagement of the T cell receptor by antigen but rather a non-specific “bystander” effect. However, in an accompanying commentary Zvi Grossman notes that the data do not necessarily entirely rule out a role for direct T cell activation by HIV and/or other microbial antigens. This distinction may seem arcane, but because T cell activation correlates with disease progression it is critically important to understand the exact cause (or causes) of this phenomenon. Grossman also offers a schematic drawing representing the potential impact of HIV infection on the lymph node environment.
Grossman concludes by saying: “Are the changes in the cellular and cytokine profiles in secondary lymphoid organs truly ‘abnormal,’ or are they essentially reversible manifestations of immune activation and its physiological controls? To what extent do they reflect irreversible tissue destruction and loss of function? A better understanding of these issues may reveal, in the authors' words, ‘new targets for immune-based interventions to slow HIV-1 disease progression.’”
Blood, 15 May 2007, Vol. 109, No. 10, pp. 4116-4117 (full text available free)
Looking at HIV-infected lymph nodes
Zvi Grossman, Tel Aviv University
Blood, 15 May 2007, Vol. 109, No. 10, pp. 4272-4279
Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1
Angélique Biancotto1, Jean-Charles Grivel1, Sarah J. Iglehart1, Christophe Vanpouille1, Andrea Lisco1, Scott F. Sieg2, Robert Debernardo2, Kristen Garate2, Benigno Rodriguez2, Leonid B. Margolis1, and Michael M. Lederman2
1 Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, MD; 2 Center for AIDS Research, Case Western Reserve University/University Case Medical Center, Cleveland, OH
There is growing recognition that HIV-1 infection leads to an activation of the immune system that includes perturbations of cytokine expression, redistribution of lymphocyte subpopulations, cell dysfunction, and cell death. Here, we explored the relationships between HIV-1 infection and immune activation in chronically HIV-1–infected human lymph nodes. In addition to CD4 T-cell depletion, we found increased effector T-cell frequencies associated with profound up-regulation of an activation marker CD38 in naive, central memory, and effector CD4+ and CD8+ T cells. Likewise, Fas death receptor (CD95) was more frequently detectable on T cells from HIV-1 nodes. Dendritic cell (DC) depletion was dramatic, with plasmacytoid DCs (PDCs) 40-fold and myeloid DCs (MDCs) 20-fold less frequent in HIV+ nodes than in control nodes. Cytokine dysregulation was evident, with IL-2 and IL-15 as much as 2 or 3 logs greater in infected nodes than in control nodes. Thus, activated effector cells are inappropriately attracted and/or retained in lymphoid tissue in chronic HIV-1 infection. High-level cytokine expression in turn activates and retains more cells at these sites, leading to lymphadenopathy and massive bystander activation that characterizes HIV-1 infection. Strategies targeting these activation pathways may lead to new therapies.
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