Infection with Brugia microfilariae induces apoptosis of CD4+ T lymphocytes: a mechanism of immune unresponsiveness in filariasis

• Published in: European journal of immunology 2002-03, Vol.32 (3), p.858-867
• Main Authors: Jenson, Jessica S., O'Connor, Richard, Osborne, Julie, Devaney, Eileen
• Format: Article
• Language: English
• Subjects: Aedes - parasitology; Animals; Antigens, Helminth - immunology; Apoptosis; Brugia pahangi - growth & development; Brugia pahangi - physiology; Carboxyfluorescein diacetate succinimidyl ester; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - secretion; Cells, Cultured - drug effects; Effector T cell; Enzyme Inhibitors - pharmacology; Filariasis - immunology; Filariasis - pathology; Flow Cytometry; Fluoresceins - analysis; Fluorescent Dyes - analysis; Gerbillinae; Guanidines - pharmacology; IFN‐γ; Immunologic Deficiency Syndromes - etiology; Immunologic Deficiency Syndromes - parasitology; Inducible nitric oxide synthase; Interferon-gamma - biosynthesis; Mice; Mice, Inbred BALB C; Microfilariae - physiology; Nitric Oxide - physiology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - physiology; Nitric Oxide Synthase Type II; Parasitemia - immunology; Parasitemia - pathology; Spleen - pathology; Succinimides - analysis; Th2 Cells - immunology; Th2 Cells - secretion
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200203)32:3<858::AID-IMMU858>3.0.CO;2-E

In humans infected with lymphatic filariasis, microfilaraemia [the presence of microfilariae (Mf) in the blood] is generally associated with both poor antigen (Ag)‐specific proliferative responses and with protection from severe disease. Clonal deletion has been suggested as one possible mechanism by which parasite‐reactive lymphocytes, that may be capable of mediating resistance and / or immunopathology, are silenced in asymptomatic carriers. In this study we demonstrate that splenic lymphocytes from mice infected with microfilariae of Brugia pahangi display an Ag‐specific proliferative defect. However, these cells were not completely unresponsive since they produced high levels of Ag‐specific IFN‐γ. Using TdT‐mediated dUTP‐biotin nick end labeling for flow cytometry, CD4+ lymphocytes from Mf‐infected mice cultured with Ag showed high levels of apoptosis when compared to those from L3‐infected mice which proliferated well in response to Ag. Treatment of Ag‐stimulated cultures with aminoguanidine (AMG), an inhibitor of inducible nitric oxide synthase, rescued the CD4+ T cells from apoptosis and reversed the proliferative defect. Furthermore, carboxyfluorescein diacetate succinimidyl ester labeling allowed the visualization of dividing CD4+ T cells in cultures from Mf‐infected animals only in the presence of AMG. We hypothesize that CD4+ T cells indirectly trigger their own apoptosis by secreting significant quantities of IFN‐γ resulting in the induction of high levels of nitric oxide, and the subsquent elimination of effector T cells. Our findings are the first direct evidence that infection with Brugia Mf can selectively induce lymphocyte apoptosis, a phenomenon that could contribute to the proliferative defect and parasite persistence associated with the microfilaraemic state in the infected human.