The objective of this project is to examine T regulatory cells (Tregs) in Rhesus macaques (Rh) and African green monkeys (AGMs). Tregs, initially defined as CD4+CD25+, suppress T-cell activation and proliferation in mice and humans. As chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic HIV/SIVmac infections in humans and Rh, these cells may play an important role in HIV/SIV pathogenesis. Rh and AGMs, the best models for the study of SIV pathogenesis, differ in one fundamental aspect: Rh infected SIVmac develop AIDS, while AGMs infected with SIVagm typically remain healthy. Our preliminary studies showed a loss of CD4+CD25+ T cells in SIVmac-infected Rh that may explain the aberrant chronic T cell hyperactivation described in this pathogenic infection. In contrast, we have found an increase in the number of Tregs during very early stages of SIVagm infection and a better preservation of CD4+CD25+ T cells in chronically SIVagm-infected AGMs. The pattern of CD4+CD25+ T cell dynamics in SIVagm-infected AGMs corroborates the lack of immune activation and turnover during SIV infection in natural hosts. We therefore hypothesize that fully functional Tregs are present in non-human primates and may play a protective role in SIV infection. To clearly define the role of Tregs in pathogenic and non- pathogenic SIV infections, we designed experiments in this proposal for normal and SIV-infected Rh and AGMs, to confirm the existence of functional Tregs and to verify our ability to manipulate this T cell subset. We propose the following Specific Aims (SA): SA1: To characterize Tregs in normal and SIV-infected Rh and AGMs. CD25 is not a specific marker for Tregs; it is also upregulated upon conventional T cell activation. Our proposal will therefore focus on identification of specific markers for Tregs such as FOXP3, GITR, CD223 and neuropilin-1 in association with previously studied CD4+CD25+ T cells and also on determining the in vitro suppressive functions of T cell subsets identified with these markers, that have never been studied in non-human primates (NHP). SA2: To determine the distribution of Tregs in tissues of normal and SIV-infected Rh and AGMs. CD4+CD25+ cells from peripheral blood might represent only a small portion of the total Tregs. In order to focus our future SIV studies, we intend to determine the density and function of Tregs in lymph nodes (LNs), lung and intestine in both Rh and AGMs. SA3: To verify the ability of available anti-CD25 blocking/depleting drugs to eliminate Tregs in Rh and AGMs. Elimination of Tregs or Treg function in SIV-infected Rh and AGMs will enhance our knowledge about the role of this T cell subset in pathogenic and non-pathogenic SIV infections. If this specific aim will establish that this experiment is possible in normal NHPs, we will further assess the impact of Treg depletion on viral replication in chronically SIVagm-infected AGMs. Combined, these aims are designed to characterize and manipulate simian Tregs. This data will be critical for future studies examining the role of these cells in AIDS pathogenesis and may also open numerous avenues for the study of Tregs in other infectious or immune diseases for which Rh and AGMs are used as models. ? ? ?
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