HIV-infected individuals develop a marked CD8+ alveolar lymphocytosis early in the course of their illness. This is initially composed of cytotoxic T lymphocytes (T ctl), many of which are HIV-specific T ctl. T ctl are capable of causing injury to the lung, and the intensity of HIV-related CD8 alveolitis correlates with respiratory symptoms and clinical findings. CD8+ lymphocytes may accumulate in the lung through recruitment from the circulation and/or through in situ proliferation. To test the former possibility we will assess the in vitro ability of blood lymphocytes from HIV patients to adhere and migrate across an endothelial cell monolayer into a collagen matrix. Using blocking antibodies we will also assess which adhesion molecules are important in these process. We will determine whether specific chemokines, which promote the chemotaxis of CD8+ lymphocytes from the circulation are produced by alveolar macrophages from HIV patients versus controls. We will determine if alveolar CD8+ cells from HIV patients without respiratory illness are spontaneously proliferating, by nuclear DNA staining and flow cytometric analysis. In situ proliferation of CD8 cells in HIV patients may be driven by local over-expression of transforming growth factor (TGF)-B1. We will determine if TGF-beta 1 is produced by alveolar macrophages from HIV patients, if it is active by bioassay, and stimulates autologous CD8+blood T cells proliferation. Using in situ hybridization we will determine if TGF-Beta1 mRNA is detectable in lung biopsy specimens from HIV patients with lymphocytic interstitial pneumonia and compare them with normal lung tissue. Although CD+ alveolitis persists as HIV infection progresses, it is unclear why T decline in percentage, HIV-specific cytotoxicity wanes, and CD8+cells capable of negatively regulating other lymphocytes emerge. We have recently identified a unique population of CD8+ CD28-T cells that are markedly increased in the blood and, especially, lung of HIV patients. We will determine if CD8 CD28T cells from HIV patients preferentially migrate across endothelium in vitro to account for their prominence in HIV lung. Finally, we will assess the function of CD8 CD28T cells in terms of their cytolytic ability, their ability to suppress HIV-specific and other T, as well as to inhibit the production of T 1 cytokines by CD4+ cells through IL-4. The prominence of CD8 CD28- T cells in HIV patients lungs suggests these cells may contribute to immunopathogenesis of T cell dysfunction in HIV infection.
| Saukkonen, Jussi J; Bazydlo, Beth; Thomas, Michael et al. (2002) Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Infect Immun 70:1684-93 |
| Yet, S F; Perrella, M A; Layne, M D et al. (1999) Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 103:R23-9 |
| Saukkonen, J J; Tantri, A; Berman, J (1999) Costimulation of CD28- T cells through CD3 and beta1-integrins induces a limited Th1 cytokine response. Scand J Immunol 50:145-9 |
| Saukkonen, J J; Furfaro, S; Mahoney, K M et al. (1997) In vitro transendothelial migration of blood T lymphocytes from HIV-infected individuals. AIDS 11:1595-601 |
