Date Published: June 27, 2013
Publisher: Public Library of Science
Author(s): Vasudha Sundaravaradan, Ramsey Saleem, Luca Micci, Melanie A. Gasper, Alexandra M. Ortiz, James Else, Guido Silvestri, Mirko Paiardini, John D. Aitchison, Donald L. Sodora, Daniel C. Douek.
Studying SIV infection of natural host monkey species, such as sooty mangabeys, has provided insights into the immune changes associated with these nonprogressive infections. Mangabeys maintain immune health despite high viremia or the dramatic CD4 T cell depletion that can occur following multitropic SIV infection. Here we evaluate double-negative (DN)(CD3+CD4−CD8−) T cells that are resistant to SIV infection due to a lack of CD4 surface expression, for their potential to fulfill a role as helper T cells. We first determined that DN T cells are polyclonal and predominantly exhibit an effector memory phenotype (CD95+CD62L−). Microarray analysis of TCR (anti-CD3/CD28) stimulated DN T cells indicated that these cells are multifunctional and upregulate genes with marked similarity to CD4 T cells, such as immune genes associated with Th1 (IFNγ), Th2 (IL4, IL5, IL13, CD40L), Th17 (IL17, IL22) and TFH (IL21, ICOS, IL6) function, chemokines such as CXCL9 and CXCL10 and transcription factors known to be actively regulated in CD4 T cells. Multifunctional T-helper cell responses were maintained in DN T cells from uninfected and SIV infected mangabeys and persisted in mangabeys exhibiting SIV mediated CD4 loss. Interestingly, TCR stimulation of DN T cells from SIV infected mangabeys results in a decreased upregulation of IFNγ and increased IL5 and IL13 expression compared to uninfected mangabeys. Evaluation of proliferative capacity of DN T cells in vivo (BrDU labeling) indicated that these cells maintain their ability to proliferate despite SIV infection, and express the homeostatic cytokine receptors CD25 (IL2 receptor) and CD127 (IL7 receptor). This study identifies the potential for a CD4-negative T cell subset that is refractory to SIV infection to perform T-helper functions in mangabeys and suggests that immune therapeutics designed to increase DN T cell function during HIV infection may have beneficial effects for the host immune system.
While simian immunodeficiency virus (SIV) infection of Asian macaques generally results in progression to simian AIDS, SIV infection of African monkey species is typically associated with a nonpathogenic outcome. These African monkeys, including sooty mangabeys, are found naturally infected with SIV and are thought to have evolved with their species-specific viruses . Studies of SIV infections of mangabeys and African green monkeys have provided key insights into the evolutionary mechanisms enabling these monkey species to remain free of disease. A number of studies have established that plasma viral levels are similar between natural SIV hosts and pathogenic infections observed in Rhesus macaques and HIV infected patients –. The SIV-specific antibody and cytotoxic T-lymphocyte (CTL) levels are also generally similar between the hosts of natural and pathogenic infections, indicating that stronger or more effective adaptive immune responses are not responsible for the non-pathogenic disease course , . A major difference between natural and pathogenic infection is the lack of systemic immune activation (measured by proliferation/activation of immune cells, plasma cytokine levels) in the natural hosts during the chronic phase of the infection , –. How the natural hosts are able to suppress activation following the acute infection phase and why the natural hosts do not progress to simian AIDS despite high levels of viral replication are current avenues of research to understand SIV/HIV infection and host response.
This study demonstrates that (CD3+CD4−CD8−) DN T cells possess Th1, Th2, Th17 and TFH function in sooty mangabeys irrespective of SIV infection. We expand upon previous findings by performing an in-depth analysis of DN T cell functions using transcriptomic as well as flow cytometric analyses, and now define how these functions are altered during SIV infection and SIV mediated CD4 T cell loss. DN T cells are refractory to SIV-infection , which likely aids their ability to maintain function and proliferative capacity during SIV infection and the subsequent CD4 depletion observed in the CD4-low mangabeys , , . We identify DN T cells as a polyclonal T cell subset with a predominantly EM cell phenotype, maintained proliferative capacity, and with a specific increase in the proportion of EM DN T cells. Further, we show that they have the ability to respond to SIV specific antigens presented in the context of both MHC-I or MHC-II. Previous studies have demonstrated that during SIV infection of mangabeys, CD4 T cells retain a CM phenotype and this preservation of CM T cells has been implicated as one of the mechanisms by which mangabeys are able to inhibit progression to simian AIDS . Since EM CD4 T cells are infected at greater frequency than CM CD4 T cells in the sooty mangabeys, the DN T cells, which are refractory to SIV infection, may therefore perform T helper effector functions and serve as workhorses for the mangabey immune system, with a potential to function during SIV infection.