Multifunctional Double-negative T Cells in Sooty Mangabeys Mediate T-helper Functions Irrespective of SIV Infection

Abstract

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.

Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection

“…DN T-cells are associated with reduced immune activation and high levels of immune-suppressive cytokines, including TGF-b and IL-10, in HIV infection (Petitjean et al, 2012). In simian immunodeficiency virus (SIV) infection of non-human primates, DN T-cells are capable of performing CD4 + T-cell-like helper functions whilst remaining refractory to SIV infection and are associated with a lack of clinical disease progression (Milush et al, 2011;Sundaravaradan et al, 2012Sundaravaradan et al, , 2013. Thus, the increased numbers of DN T-cells in HPgV infection may play important roles in reducing immune activation and maintenance of immune homeostasis, contributing to improved survival in HIV co-infection.…”

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

“…In sooty mangabeys, double-negative T cells, which express neither CD4 nor CD8, are thought to be responsible for the lack of disease progression in a subset of animals that undergo severe CD4 ϩ T cell depletion (11)(12)(13). Furthermore, there is evidence that CD4 downregulation and the large population of CD8␣␣ T cells observed in Patas monkeys led to the extinction of a Patas-specific SIV (14).…”

Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice

“…Additionally, Mou et al have shown that major histocompatibility complex (MHC) class II-restricted DN T cells contribute to optimal immunity against Leishmania major in mice (23). For simian immunodeficiency virus (SIV) infections, Sundaravaradan and colleagues reported that multifunctional DN T cells mediated a T helper cell function during SIV infection of mangabeys; these animals remained healthy despite high viremia and CD4 ϩ T cell depletion (24). While the role of DN T cells in protecting humans against microbial pathogens is less clear, DN T cell populations have been shown to expand during staphylococcal and mycobacterial infections (21,25).…”