The Role of the B7 Co-stimulation Pathway in Feline Immunodeficiency Virus (FIV) and Human Immunodeficiency Virus (HIV)Associated T cell depletion

Abstract

Feline immunodeficiency virus (FIV) in the domestic cat provides a good animal model for dissecting the immunopathology associated with HIV infected individuals, as the immune dysfunction in the cat replicates the immune deterioration in humans. Lentiviruses characteristically cause a gradual loss in T-helper cells numbers and functions. A variety of mechanisms have been proposed to account for lentivirus-induced T cell depletion although none of these mechanisms alone account for all the T cell changes.

The B7/cytotoxic T lymphocyte antigen four (CTLA4) signaling pathway is a major signaling pathway in the initiation and termination of T cell immune responses. The B7 receptors are normally expressed on the surface of antigen presenting cells (APC), while CD28 and CTLA4 are differentially expressed on the surface of T cells. Recent studies show that chronic stimulation in vitro or in vivo results in an unusual increase in the percent of T cells that express the B7 and CTLA4 molecules. These chronically activated T cells also up-regulate major histocompatibility complex class II molecules (MHC II) and are capable of inducing anergy and apoptosis of other activated T cells. In this study we found that individuals with a HIV or FIV infections had increased expression of B7 and CTLA4 on T cells in peripheral blood and lymph nodes (LN). These B7+CTLA4+ T cells were associated with an increased frequency of spontaneous apoptosis. Analysis of MHCII receptor expression on PBMC from HIV infected patients revealed a significant increase in MHCII+ expression on B7+ or CTLA4+ T cells. TUNEL analysis of B7+MHCII+ or CTLA4+MHCII+ compared to B7+MHCIIneg or CTLA4+MHCIIneg T cells revealed that the increased frequency of T cell apoptosis could almost exclusively be attributed to B7+MHCII+ and CTLA4+MHCII+ T cells, similar to our observations in the cat From these data we hypothesize that T: T interactions between CD4+ and CD8+ B7+CTLA4+MHCII+ T cells within the LN results in IL2 inhibition rendering them susceptible to cytokine deprived apoptosis.