Exhaustion of Regulatory T Cell Subsets Induces B Cell Dysfunction in HIV Subjects
Jennifer Snyder-Cappione, J. David Gladstone Institutes
Biomedical and Clinical Sciences
Background: B cell hyperactivity, including hypergammaglobulinemia, is very common in HIV infected subjects. Interestingly, higher serum immunoglobulin titers are associated with rapid loss of CD4 T cells; this is believed to be due to increased formation of autoimmune complexes, which often contain the gp120 antigen and specifically target CD4 T cells for apoptosis. We hypothesize that regulatory T cells (Treg, NKT cells) directly suppress activation, proliferation, and immunoglobulin secretion by B cell populations. We propose that B cell aberrancies, including hypergammaglobulinemia and the excess of gp120-specific antibodies present in many persons infected with HIV, are a direct result of regulatory T cell dysfunction in these patients. It may be possible to abrogate the B cell dysfunctions present in many HIV-infected patients through enhancement of the suppressive mechanisms of regulatory T cells; this could lead to the generation of novel therapies that alter the frequencies and /or effector functions of regulatoryT cells to reduce and/or prevent both CD4 T cell loss (induced by antibody complexes) and B cell diseases, including autoimmune disorders and lymphomas, that are present in afflicted individuals.
Methods: The frequencies of ASCs will be enumerated using IgG, IgM, and IgA Elispot assays. These assays can measure the total number of Ig secreting cells, as well as the frequencies of ASC secreting antibodies for specific viral or protein antigens. Total plasma titers for Ig isotypes will be measured by ELISA. The frequencies and functions of Treg and NKT populations will be evaluated by Flow Cytometry and Elispot assays.
Results/ Expected Results: Preliminary data suggestTreg cells are capable of directly inhibiting immunoglobulin secretion from ASCs in vitro. This novel 'B regulatory' effector function of Treg cells will be evaluated from PBMC of acute and chronic HIV-infected individuals to determine if there is a correlation between the ex vivoeffector functions of regulatoryT cell populations and the presence of B cell disorders, including lymphomas, found in many HIV-infected individuals. A subset of these infected patients will be studied longitudinally to determine if ex vivo Treg / NKT cell frequencies/functions are related to the rate of CD4 T cell loss and progression to AIDS.