Treg exhaustion induces B cell dysfunction in HIV+ subjects
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: B lymphocytes (B cells) are immune cells that release immunoglobulins, proteins that protect against a variety of infections. However, when immunoglobulins that are specific for one’s own proteins are released they often contribute to the development of autoimmune diseases. Many people infected with HIV have over-activated B cells, and as a result develop a variety of autoimmune diseases and well as B cell cancers. Another immune cell, a T regulatory cell, has been shown to prevent the development of autoimmunity in both mice and humans, and also contributes to the immune response to many infectious diseases, including HIV. Little is known about the ability of T regulatory cells to suppress B cell responses. The experiments in this proposal will investigate the novel paradigm that T regulatory cells directly suppress immunoglobulin secretion from B cells. The frequencies of T regulatory and Antibody Secreting Cells (ASC) within the blood of HIV infected people will be measured to determine whether T regulatory cell deficiencies correlate with the acquisition of B cell lymphomas and /or autoimmune diseases. There are many small organs throughout the body called lymph nodes. It is within lymph nodes that immune cells will recognize the HIV virus and the T and B cells will become activated to combat the spread of infection. HIV is a unique infection because it infects one type of T cell called a CD4 cell. These CD4 T cells move to lymph nodes, and then the organ where the immune cells need to be activated are also exposed to a large degree of inflammation because the active virus is present. We hypothesize the inflammatory signals may cause T regulatory cells to become overwhelmed and be unable to effectively prevent activation of bystander B cells that contain immunoglobulins specific for self proteins. Biopsies of lymph nodes will be obtained from people shortly after they are first infected with HIV, and the location of T regulatory cells and B cells and their activation markers will be measured though the use of fluorescent antibodies. In addition, recent studies suggest the loss of CD4 T cells that ultimately cause HIV infected- people to progress to AIDS may be primarily due to binding of CD4 T cell to complexes of immunoglobulins present in the bloodstream. These complexes target the CD4 cell to be destroyed by other components of the immune system. We will measure the rate of CD4 T cell loss in many HIV infected patients over time, and compare the frequencies and functions of T regulatory cells and ASC to these changes in CD4 counts to determine if loss of T regulatory cell activity is related to faster progression to AIDS due to increased immunoglobulin secretion. This research could facilitate the development of novel therapies that alter the frequencies/functions of T regulatory cells to eliminate B cell hyperactivity. Such treatments could prevent the development of autoimmune diseases and B cell lymphomas, as well as significantly abrogate the loss of CD4 T cells in HIV-infected patients, to substantially extend the length and quality of life of HIV-infected persons living in California.