An interesting new basic immunology paper in PNAS suggests that decreased naïve T cell numbers are associated with microbial translocation (the transfer of normally harmless “friendly” gut bacteria across the mucosa) and that this, in turn, exacerbates naïve T cell depletion by causing immune activation. The authors argue that the output of naïve T cells by the thymus is required for the maintenance of immunological détente with gut bacteria and that the cessation of thymic output (induced artificially in this paper by genetic manipulation and the administration of poly I:C) disrupts this balance leading to increases in lipopolysaccharide binding protein (LBP) that are indicative of microbial translocation in mice. Microbial translocation has recently been implicated as a cause of immune activation in HIV infection, but the cause has been suggested to be early depletion of gut "memory" CD4 T cells. This new paper suggests that the depletion of naive T cells - a well-described consequence of HIV infection - could also contribute.
The study may also have implications for efforts to untangle the relationship between cause and effect when it comes to immune activation in HIV infection; data indicates that persistent immune activation despite ART is associated with poor immune reconstitution and the general assumption has been that the activation is playing a causative role. This new data suggests that immune activation could also possibly result from poor immune reconstitution (e.g. slow naïve T cell repletion due to poor thymic output). Therapies such as IL-7, which recent studies indicate can enhance naïve T cell repletion, might therefore conceivably reduce immune activation, and this can be explored in ongoing and planned studies.
Published online on June 18, 2008, 10.1073/pnas.0803732105
PNAS | June 24, 2008 | vol. 105 | no. 25 | 8691-8696
Article
BIOLOGICAL SCIENCES / IMMUNOLOGY
Christine Bourgeois*,, Zhenyue Hao, Klaus Rajewsky,¶, Alexandre J. Potocnik*, and Brigitta Stockinger*,¶
*Division of Molecular Immunology, The National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Research Institute, Toronto, ON, Canada M5G2C1; and Immune Disease Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115
Contributed by Klaus Rajewsky, April 17, 2008 (received for review March 4, 2008)
A model of chemical thymectomy by inducible Rag ablation was used to study peripheral T cell homeostasis. Induction of Rag ablation was efficient and complete, leading to cessation of thymic T cell production within 3–4 weeks. The decay of peripheral T cells became apparent with a delay of an additional 2–3 weeks and was entirely accounted for by loss of naïve T cells, whereas numbers of memory phenotype and regulatory T cells were not decreased. Naïve CD4 T cells decayed with an average half-life of 50 days, whereas naïve CD8 T cells exhibited a considerably longer half-life. The rapid decay of naïve CD4 T cells was not caused by intrinsic survival differences compared with naïve CD8 T cells, but was caused by changes in the lymphopenic environment resulting in higher microbial load and consequential activation. This finding suggests that in lymphopenic conditions involving compromised thymic function replenishment and survival of a naïve CD4 T cell repertoire may be severely curtailed because of chronic activation. Such a scenario might play a role in the aging immune system and chronic viral infection, such as HIV infection, and contribute to loss of CD4 T cells and impaired immune function. As our data show, continued replenishment with cells from the thymus seems to be required to maintain efficient gut mucosal defense.
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