Regulatory T cells (Treg), a subset of CD4+ T cells, are required both to establish and sustain immunological self-tolerance. We have shown during chronic infections, such as HIV infection, that Treg accumulate and they preserve their functionality (JI, 2005; Blood, 2006; J Virol, 2007). We have also shown that Treg act as double-edge sword during HIV infection, blunting immune responses (Blood, 2006), but also decreasing T cell and dendritic cell infection by HIV (Blood, 2012; Front Immunol, 2014). In addition, we study the effect of highly active antiretroviral therapy on Treg function and homeostasis (PLoSOne, 2011, and 2013).
Our lab also studies Treg biology in other settings. Treg develop very early during the ontogeny of the human infant immune system and their disappearance and/or dysfunction is likely to play a role in the debilitating inflammatory diseases that premature neonates developed, such as Broncho-Pulmonary Dysplasia or Necrotizing Enterocolitis. Importantly, over 50% of very preterm births have an antecedent infection associated with chorioamnionitis or premature rupture of membranes. In collaboration with Drs. Alan Jobe and Suhas Kallapur in the Division of Neonatology, we are actively pursuing this line of research focusing on the effect of chorioamnionitis on Treg homeostasis and function, either in nonhuman primate experimental models (JI, 2013) or in human cohorts (Hum Immunol, 2014). We also collaborate with Dr. Alex Miethke in the Division of Gastroenterology and Nutrition to study the role of Treg in biliary atresia (J Hepatol, 2010, Hepatology, 2012).
We have shown that Treg homeostasis is changed during aging, leading to increased survival and accumulation in lymphoid organs (JI, 2008; JI, 2011; Front Immunol, 2013). We are now deciphering the underlying mechanisms as Treg accumulation is an important contributing factor to immunosenescence.
To better study human Treg function, we have developed advanced phenotypic strategies (Cytometry A, 2010) and assays that probe Treg suppressive action on dendritic cells and their capacity to activate conventional T cells, using imaging flow cytometry (Figure 1 and Front Immunol, 2014).
- NIH R01 AG033057 (co-PIs: C. Chougnet/D. Hildeman) Homeostasis and function of regulatory T cells in aging.
- NIH U01HL101800 (co-PIs: A. Jobe/C. Chougnet) Biomarkers of Immunologic Function and Preterm Respiratory Outcomes.
- NIH R01HD078127 (co-PIs: L. Muglia/C. Chougnet) Maternal temperament, stress, and inflammation in preterm birth.
- Burrough-Wellcome fund (PI: C. Chougnet) Host-microbe cross talk and pregnancy outcomes.
- Cincinnati Children's RIP (PI: C. Chougnet) Mechanisms underlying High Density Lipoprotein-mediated survival of human regulatory T cells.
Analysis of human Regulatory T cell (Treg) function.
We developed assays that probe Treg suppressive activity on dendritic cell (DC)-mediated l stimulation of conventional T cells (Tcon). Treg were added or not to DC and Tcon cultures at a physiological ratio of 1:10:1(DC:Tcon:Treg) ratio. (A) 3 populations can be visualized by imaging flow cytometry: (1) isolated DC (HLA-DR+ cells), (2) isolated Tcon (CellTraceTM-Violet+ cells) and (3) DC:Tcon aggregates (CellTraceTM-Violet+HLA-DR+ population). (B) Actin polymerization at the immunological synapse forming between DC and Tcon. (C) Treg control different aspects of DC-Tcon activation, decreasing the percentage of DC:Tcon aggregates in the cellular population, the percentage of activated Tcon (CD134+), the percentage of activated DC (CD83+) in aggregates and actin polymerization at the immunological synapse.