The Role Of CD4 In Macrophage Differentiation And Function
Scott G Kitchen
Medicineuniversity Of California Los Angeles
Grant 1R01AI078806-01A2 from National Institute Of Allergy And Infectious Diseases IRG: AIP
Abstract: The CD4 molecule has an important role in the human immune system and in the pathogenesis of HIV. A key factor in HIV pathogenesis is the use of the CD4 molecule as the primary receptor for cellular infection. In addition to CD4+ T helper cells, there are numerous other cells of the immune system that express CD4 that are susceptible to infection by HIV. One of the primary targets and an important and poorly understood reservoir for HIV in an infected individual are monocytes/macrophages. Other than allowing HIV infection of these cells, the role of the CD4 receptor in the function and development of monocyte/macrophages is not known. We have recently determined that ligation of CD4 on monocytes/macrophages modulates gene and cytokine protein expression as well as T cell responses. We are interested in examining this and other roles and functions of the CD4 molecule on the monocyte/ macrophage cell subset. Our central hypothesis in this proposal is that CD4 has a role in monocyte/ macrophage differentiation and function by modulating the expression of factors that control cellular development and other immune responses. This, in turn, has important implications in HIV infection and the understanding of the monocyte/ macrophage reservoir of infected cells in disease progression. This proposal will focus on addressing these issues and will focus on the following three Specific Aims 1. To determine the mechanisms regulating CD4 expression during monocyte/macrophage development. 2. To determine the function(s) and consequence(s) of CD4 expression during monocyte/macrophage lineage differentiation and development. 3. To determine the role(s) of the CD4 molecule on mature monocyte/ macrophage function. To achieve this, we will utilize a novel embryonic stem cell-based system that we can genetically manipulate and examine monocyte/ macrophage differentiation and function from a cell type that is among the earliest in human hematopoietic development. In summary, it is anticipated that these studies will shed light on the potential roles and importance of CD4 in monocyte/macrophage development and/or function. Further, it is anticipated that the proposed studies will allow a more comprehensive understanding of the consequences of HIV infection in this cell type. The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases
Project start date: 2009-07-01
Project end date: 2014-06-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Scott G Kitchen
The Role Of CD8 On CD4+ T Cells
Scott G Kitchen
University Of California Los Angeles Office Of Research Administration Los Angeles, Ca 90095
Grant 5R21AI057057-02 from National Institute Of Allergy And Infectious Diseases IRG: AARR
Abstract: There are many mechanisms that contribute to the decline of the immune response in HIV disease. Infection and perturbation of CD4+ T cells by HIV dramatically contributes to viral replication and a decreased ability to respond to antigenic insult. There are many different functional subsets of CD4+ T cells, and HIV appears to target the highly activated populations, particularly those cell that specifically respond to HIV infected cells. We have shown that CD4 expression by CD8+ T cells plays an important role in CD8 cell function. Recently, our laboratory has identified a highly activated population of CD4+ T cells that express the CD8 molecule. Preliminary studies indicate that this population is more abundant in HIV-infected people and may reflect the greater levels of cellular activation seen in these individuals. This high level of activation could render these cells more susceptible to infection and destruction by HIV. This proposal describes studies that examine the function of this subset and the role of the CD8 molecule on CD4+ T cells. We will examine the expression of this molecule during CD4+ T cell activation, as well as the phenotypic and function characteristics of this cell type. We will investigate the following three Specific Aims 1) Further explore the acquisition of CD8 expression by CD4+ T cells, 2) Determine the function of the CD8 molecule on CD4+ T cells, 3) To examine the functional role of CD8 expression on CD4+ T cells in vivo in response to viral infection and alloantigen. The experiments outlined in this proposal will help us understand the role of CD8 on CD4+ T cells and the effects of HIV infection on this subset. Further, it will allow us to determine the function of the CD4+CD8dim subset seen in vivo. These studies combined will allow us to determine the possible effects that the appearance or loss of this subset may have on HIV disease progression and antiviral immunity.
Keywords: CD8 molecule, HIV infection, helper T lymphocyte, leukocyte activation /transformation, virus infection mechanism, HIV envelope protein gp120, cytotoxic T lymphocyte, immunoregulation, clinical research, flow cytometry, human subject, laboratory mouse, polymerase chain reaction
Project start date: 2003-08-01
Project end date: 2006-07-31
5R21AI057057-02 (2004): $230376
1R21AI057057-01 (2003): $228876