Recent research on the pathogenesis of HIV and SIV infections has identified the depletion of “central memory” (TCM) CD4 T cells as being a crucial – perhaps the crucial – factor precipitating the development of clinical immunodeficiency and AIDS. As covered previously on the blog, TCM are a subset of memory T cells endowed with the capacity for self-renewal and capable of prodigious proliferation if they encounter a pathogen that they recognize. The research group of Rafik-Pierre Sekaly at the University of Montreal recently identified the transcription factor forkhead box O3a (FOXO3a) as a key mediator of TCM survival. FOXO3a controls several genes involved in the cell cycle (the process of cell division) and apoptosis (cell death) such as bim, but when FOXO3a is phosphorylated, it is excluded from the cell nucleus and thus cannot promote expression of these genes. In their paper published in the Journal of Experimental Medicine in late 2006 (see abstract, below), Catherine Riou and colleagues showed that TCM expressed higher levels of the transcriptionally inactive phosphorylated forms of FOXO3a and, consequently, lower levels of the cell-death promoting protein Bim. They also reported that FOXO3a phosphorylation can be promoted synergistically by signaling through the T cell receptor (TCR) and cytokines known to enhance memory T cell survival such as IL-7.
Now, in paper just published online by Nature Medicine, the same group demonstrate that HIV-infected elite controllers (individuals controlling viral load to less than 50 copies in the absence of any treatment) have higher levels of phosphorylated FOXO3a in both TCM and effector memory CD4 T cells (TEM) compared to individuals on successful antiretroviral therapy (ART). Conversely, levels of the pro-apoptotic protein Bim were higher in TCM and TEM from people on ART compared to elite controllers. Consistent with these findings, TCM and TEM from elite controllers survived repeated rounds of in vitro stimulation far better than those from individuals on ART. The researchers also used various techniques to inactivate FOXO3a in TCM and TEM cells from ART-treated study subjects and found that these interventions made their in vitro lifespan comparable with TCM and TEM from the elite controllers.
In discussing the results, the authors note that it is possible signaling pathways are perturbed in the cells of individuals on ART such that the integration of TCR and cytokine signals does not cause FOXO3a phosphorylation in the normal way. They also suggest that specific genetic polymorphisms affecting cell signaling pathways could be present in elite controllers; ongoing whole-genome analyses (in a study led by Partners AIDS Research Center in Boston) will be able to address this possibility. The authors close by stating that their work confirms the importance of maintaining TCM integrity in preventing HIV disease progression, and that approaches with the potential to enhance TCM survival may deserve study as therapies for HIV infection.
Nat Med. 2008 Mar 2 [Epub ahead of print]
Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection.
van Grevenynghe J, Procopio FA, He Z, Chomont N, Riou C, Zhang Y, Gimmig S, Boucher G, Wilkinson P, Shi Y, Yassine-Diab B, Said EA, Trautmann L, Far ME, Balderas RS, Boulassel MR, Routy JP, Haddad EK, Sekaly RP.
[1] Laboratoire d’Immunologie, Centre de Recherche, Hôpital Saint-Luc, Centre Hospitalier de l’Université de Montréal, 264 Boulevard Rene-Levesque Est, Montréal, Québec H2X 1P1, Canada. [2] Laboratoire d’Immunologie, Département de Microbiologie et d’Immunologie, Université de Montréal, 264 Boulevard Rene-Levesque Est, Montréal, Québec H3T 1J4, Canada. [3] Institut national de la Santé et de la Recherche médicale U743, Centre de Recherche, Centre Hospitalier de l’Universite de Montréal, 264 Boulevard Rene-Levesque Est, Montreal, Québec H2X 1P1, Canada.
The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.
J Exp Med. 2007 Jan 22;204(1):79-91. Epub 2006 Dec 26.
Riou C, Yassine-Diab B, Van grevenynghe J, Somogyi R, Greller LD, Gagnon D, Gimmig S, Wilkinson P, Shi Y, Cameron MJ, Campos-Gonzalez R, Balderas RS, Kelvin D, Sekaly RP, Haddad EK.
Laboratoire d’Immunologie, Centre de Recherche, Hôpital Saint-Luc du Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, Québec H2X 1P1, Canada.
The molecular events involved in the establishment and maintenance of CD4+ central memory and effector memory T cells (TCM and TEM, respectively) are poorly understood. In this study, we demonstrate that ex vivo isolated TCM are more resistant to both spontaneous and Fas-induced apoptosis than TEM and have an increased capacity to proliferate and persist in vitro. Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of CD4+ TCM depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a). TCM showed a significant increase in the levels of phosphorylation of STAT5a compared with TEM in response to both IL-2 (P<0.04) and IL-7 (P<0.002); the latter is well known for its capacity to enhance T cell survival. Moreover, ex vivo TCM express higher levels of the transcriptionally inactive phosphorylated forms of FOXO3a and concomitantly lower levels of the proapoptotic FOXO3a target, Bim. Experiments aimed at blocking FOXO3a phosphorylation confirmed the role of this phosphoprotein in protecting TCM from apoptosis. Our results provide, for the first time in humans, an insight into molecular mechanisms that could be responsible for the longevity and persistence of CD4+ TCM.
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