MRC National Institute for Medical Research, London
Science for Health
Generalised immune activation as a direct result of activated CD4+ T cell killing
30 November 2009
HIV infection is characterised by immune deficiency which is triggered by the loss of CD4+ T cells, the central coordinators of the immune response. It is also associated with aberrant activation of virtually every arm of the immune system, collectively described as generalised immune activation. This atypical activation of the immune system is currently thought to be the key contributor to its dysfunction, including the loss of CD4+ T cells during HIV infection. However, the targets, if any, and the causes of this immune activation remain unclear. Competing theories have implicated high levels of HIV replication, the loss of naturally-suppressive regulatory T cells, and also increased exposure to other microbes, especially those from the intestine, as immunity declines.
George Kassiotis (pictured), from NIMR's Division of Immunoregulation, has studied how depletion of activated CD4+ T cells, the targets of immunodeficiency virus replication, affects the murine immune system, independently from the presence of the virus or microbial exposure. Working in collaboration with Dimitris Kioussis in NIMR's Division of Molecular Immunology, Manolis Pasparakis at the University of Cologne, Germany and Nigel Killen at the University of California, San Francisco, USA, he has shown that conditional virus-free killing of activated CD4+ T cells, which include both memory and regulatory subsets, was directly responsible for the development not only of immune deficiency, but also of generalized immune activation. In contrast, increased exposure to microbes in mice with conditional disruption of intestinal epithelial integrity caused activation of macrophages, a specialised phagocyte, but not of lymphocytes.
Immunologic consequences of conditional deletion of activated CD4+ T cells
Enlargement of inguinal (i), axillary (a), brachial (b), cervical (c), mesenteric (m) lymph nodes (generalised lymphadenopathy) and spleen in mice with conditional deletion of activated CD4+ T cells (DTA), compared with littermate control mice (WT).
The subset of CD4+ T cells that immunodeficiency viruses target is quite heterogeneous. It includes effector and memory T cells, which mediate immunity to infection and re-infection, and also regulatory T cells, which prevent excessive or inappropriate triggering of the immune response. Our results from the mouse models suggest that generalised immune activation during HIV infection may have the same origin as immune deficiency, namely the loss of functionally diverse CD4+ T cells. By targeting this subset of CD4+ T cells, HIV could achieve both immune deficiency and activation without having to rely on other microbes to activate the immune response.
George Kassiotis
Original article
The research findings are published in full in:
Rute Marques, Adam Williams, Urszula Eksmond, Andy Wullaert, Nigel Killeen, Manolis Pasparakis, Dimitris Kioussis and George Kassiotis (2009).
Generalized immune activation as a direct result of activated CD4+ T cell killing
Journal of Biology, 8:93. Full text of article.
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