NK-T cells are a subset of T lymphocytes that are believed to be a crucial regulatory link between innate and adaptive immunity, with increasing evidence that they play a role in autoimmune diseases, malignancies, and infectious diseases. While the mechanism of action is poorly understood, they express a semi-invariant T-cell receptor (TCR) with a Va24-JaQ rearrangement, and recognize glycolipids presented by the non- polymorphic MHC class l-like molecule CD1d. Upon triggering, NK-T cells secrete an ample repertoire of cytokines. At least two subpopulations of NK-T cells have been described: CD4+ and CD4- CDS- (DN) NK-T cells, believed to produce Thl and Th2 cytokines, and Th1 cytokines respectively. Unbalanced NK-T cell subsets or dysfunctional NK-T cells have been correlated to autoimmune conditions as multiple sclerosis and type I diabetes. A few studies have shown that CD4+ NK-T cells are targeted by HIV-1 and that there is a selective loss of CD4+ NK-T cells in the blood of HIV-1-infected individuals, raising the question of how this contributes to the immune dysregulation prominent in infection. The vast majority of studies of NK-T cells have been performed using peripheral blood. However, blood only represents about 2% of the lymphocyte pool, and gut-associated lymphoid tissue (GALT) is the largest lymphoid organ in the body and a major reservoir of HIV-1 replication. Furthermore, it has been proposed, that the mucosa is a major reservoir for NK-T cells. Thus it will be crucial to study tissues to gain a more complete picture of immunopathogenesis, and evaluate colonic mucosal cells. The overall objective of this study is a greater understanding of the effects of the HIV-1 infection on NK-T cells, by examining the quantities, phenotypes, and functions of these cells in the setting of infection. Specifically, the aims are to: 1) Analyze the phenotypes of NK-T cells from blood and from colon biopsies in uninfected control and HIV-1-infected individuals. We will use flow cytometry to quantify and phenotype these cells, and assess for a correlation to viremia in HIV-1-infected persons and 2) Analyze the function of NK-T cells from blood and colon biopsies from uninfected control and HIV-1 infected donors. We will evaluate NK-T cell proliferative capacity, cytokine production, and cytolytic function Manipulation of NK-T cells is already being tested in preclinical trials of cancer immunotherapy, and vaccine/adjuvant strategies targeting NK-T cells are in preclinical development. Exploring NK-T cells in HIV-1 infection could there have a high impact on the development of new strategies in prevention and treatment. ? ?
| Ibarrondo, F J; Wilson, S B; Hultin, L E et al. (2013) Preferential depletion of gut CD4-expressing iNKT cells contributes to systemic immune activation in HIV-1 infection. Mucosal Immunol 6:591-600 |
| Yang, Otto O; Wilson, S Brian; Hultin, Lance E et al. (2007) Delayed reconstitution of CD4+ iNKT cells after effective HIV type 1 therapy. AIDS Res Hum Retroviruses 23:913-22 |
