Human V?2V?2 T cells respond to low molecular weight isoprenoid pyrophosphate antigens and exhibit cytotoxicity against a variety of human tumors. Cells expressing this T cell receptor are depleted early in HIV disease and their loss is associated with increased risk for malignant disease and opportunistic infections in AIDS. Recently, we reported (Alexander, et al., 2008) that the subset of ??T cells expressing cell surface CD56 is potently cytotoxic against squamous cell carcinoma cell lines and resists TNF? or Fas-mediated cellular apoptosis. CD56 is regulated by the Runx1 transcription factor and increases after stimulation by common ? chain cytokines, possibly reflecting STAT 5 activation that would free Runx1 for nuclear translocation. Cell surface CD56 on V?2V?2 was a costimulatory receptor, promoting phosphorylation of Akt-1 and apoptosis resistance. Based on these and additional data, we proposed a model for the control of ?? T cell levels: Expression of CD56 and the apoptosis resistance phenotype favored accumulation of antigen- experienced cells in the circulating population and higher expression of CD56 was associated with higher baseline V?2V?2 levels. In HIV disease, there is specific depletion of V?2V?2+ cells that is presumed to occur by indirect mechanisms because the cells do not express CD4 and are not susceptible to HIV infection in vitro. To date, the mechanism for depletion is not known. Our recent studies revealed phenotypic differences in those V?2V?2 cells remaining in HIV+ individuals (concentrating on donors with >300 CD4 T cells/mm3), including a significantly decreased capacity for expressing CD56 after cytokine stimulation. Without CD56 we predict lower Akt-1 phosphorylation and an apoptosis-sensitive phenotype. In the pre-apoptotic environment of HIV infection, sensitive cells would be depleted more rapidly. This is a plausible and testable model for the loss of V?2V?2 cells during HIV disease. Our proposal defines individual steps in the pathway for V?2V?2 cell activation and expression of the apoptosis-resistant phenotype and compares these mechanisms with cells from control and HIV+ donors. Control cells are manipulated to mimic the behavior of cells from HIV donors and HIV donor cells are altered to increase CD56 expression and apoptosis-resistance. Specific cytokines or alternate costimulatory molecules are substituted for CD56 and IL-2 to search for means to activate and potentially reconstitute V?2V?2 cells in HIV+ individuals. Recent studies implicated the Nef protein as an agonist for peroxisome proliferator activated receptor (PPAR) that would decrease Akt-1 activation and potentially decrease apoptosis-resistance in ???T cells. We will test Nef to determine whether this viral accessory protein has a role in the ??T cell depletion mechanism.

Public Health Relevance

During HIV infection, T lymphocytes are depleted after direct virus infection, in the case of CD4+ cells, and by indirect means for other cells that do not express the virus receptor. Our studies focus on the CD4-negative ??T cells that are depleted early in HIV disease and their loss reduces natural immunity to cancer and infectious disease. The research investigates intracellular signaling pathways that control cell functions, to uncover defects associated with HIV infection. Knowledge of these defects and potentially understanding the viral proteins responsible for these defects, is proximal to designing new therapy approaches to recover ?? T cells in persons with HIV disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Howcroft, Thomas K
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University of Maryland Baltimore
Internal Medicine/Medicine
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United States
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Pauza, C David; Cairo, Cristiana (2015) Evolution and function of the TCR Vgamma9 chain repertoire: It's good to be public. Cell Immunol 296:22-30
Li, Haishan; Pauza, C David (2013) Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells. Retrovirology 10:60
Chaudhry, Suchita; Cairo, Cristiana; Venturi, Vanessa et al. (2013) The ýýýý T-cell receptor repertoire is reconstituted in HIV patients after prolonged antiretroviral therapy. AIDS 27:1557-62
Li, Haishan; Chaudhry, Suchita; Chaudry, Suchita et al. (2013) Depletion and dysfunction of V?2V?2 T cells in HIV disease: mechanisms, impacts and therapeutic implications. Cell Mol Immunol 10:42-9
Cairo, Cristiana; Sagnia, Bertrand; Cappelli, Giulia et al. (2013) Human cord blood ?? T cells expressing public V?2 chains dominate the response to bisphosphonate plus interleukin-15. Immunology 138:346-60
Riedel, David J; Mwangi, Evelyn Ivy W; Fantry, Lori E et al. (2013) High cancer-related mortality in an urban, predominantly African-American, HIV-infected population. AIDS 27:1109-17
Boudova, Sarah; Li, Haishan; Sajadi, Mohammad M et al. (2013) Reply to Hartjen et al. J Infect Dis 208:184
Poonia, Bhawna; Pauza, C David (2012) Gamma delta T cells from HIV+ donors can be expanded in vitro by zoledronate/interleukin-2 to become cytotoxic effectors for antibody-dependent cellular cytotoxicity. Cytotherapy 14:173-81
Li, Haishan; Pauza, C David (2012) The ?4?7 integrin binds HIV envelope but does not mediate bystander killing of ?? T cells. Blood 120:698-9
Boudová, Sarah; Li, Haishan; Sajadi, Mohammad M et al. (2012) Impact of persistent HIV replication on CD4 negative V?2V?2 T cells. J Infect Dis 205:1448-55

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