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We received a NIDA Avant-Garde award that will allow us to play an important role in the ongoing science of HIV vaccine development. This project will focus on preventing natural killer cells from destroying activated helper CD4 cells, to strengthen vaccine effectiveness. The CD4 helper cells support the functioning of the immune system against infections, including HIV. A vaccine that enhances the immune system’s long-term ability to resist infection could enhance the antibodies against HIV and delay progression to AIDS in vulnerable populations. This will be particularly valuable among drug users who are much less likely to be treated and to have some of the worst outcomes.
Although it is clear that NK cells can kill a subpopulation of activated CD4 T cells, the defining characteristics of this target population from an NK cell point-of-view are unknown. Moreover, work from other labs has suggested that macrophages, dendritic cells, CD8 T cells, and even B cells may be potential targets of NK cells. In addition to sorting out the physiological relevance of these target cell populations in our virus infection model systems, we aim to determine the receptor-ligand interactions that control this killing activity. The cytolytic function of NK cells is dictated by the net signaling input of a variety of activating and inhibitory cell surface receptors. There is a need to carefully evaluate the expression of NK cell receptors, their ligands, and associated adaptor proteins at various times after infection. Thereafter, we can examine which pathway or changes in protein expression are required for NK cell lytic function in this immunoregulatory capacity. These studies currently involve projects centered on the identification of a ligand for an activating receptor that might be up-regulated on activated cells to make them susceptible to NK cell lysis. Further, a separate project has focused on changes in inhibitory receptor ligand expression which may imbue certain subpopulations of lymphocytes with resistance to NK cell killing.
NK cell killing of T cells is a generalizable phenomenon in a wide variety of virus infections, but has not been observed after inoculation with every virus tested. We suspect that dissimilarities in the inflammatory cytokine milieu associated with different infections contribute to the occurrence or lack thereof of NK cell immunoregulation. An improved understanding of the conditions and stimuli that dictate NK cell lysis of T cells should aid in determining whether particular immune interventions, including therapeutic administration of pro-inflammatory cytokines, would trigger this function of NK cells.
NK cells target CD4 T cells, which are required for an optimal humoral immune response and the induction of CD8 T cell memory. Therefore, we began an evaluation of the effect that NK cells have on the induction of protective immune memory after acute infections or administration of vaccines. There is an interest in how NK cells may modify germinal center responses that facilitate isotype switching and affinity maturation of antibodies as well as the differentiation of B cells into long-lived plasma cells. Likewise, we aim to determine whether NK cells influence the quality, quantity, and localization of memory T cell responses.
As part of the Center for Autoimmune Genomics and Etiology, our lab works closely with other labs in our department to determine: 1) how genetic changes associated with autoimmune disease incidence may impact the functionality of cells of the immune system, including NK cells; 2) how virus infection and host immunity interface in the development of autoimmune disease; and 3) whether the immunoregulatory activity of NK cells is vital to prevention of autoimmune disease. When disease-associated SNPs are identified that may impact antiviral immunity or NK cell immunoregulation, we aim to provide in vivo model systems to evaluate the mechanisms and potential impact of these genetic lesions. Moreover, we use murine models of autoimmune disease to dissect the impact of the immune regulatory activities of NK cells on the pathogenesis of autoimmunity.
We are currently exploring the ability of NK cells to continually suppress adaptive antiviral immune responses during chronic infection. Conceivably, therapeutic depletion or suppression of NK cell immunoregulatory activities could rescue functionally impaired virus-specific T and B cells, thereby permitting enhanced immune-mediated control of viral replication and perhaps limiting diseases associated with viral persistence (hepatitis and AIDS). In a similar fashion, NK cells may be harnessed in adoptive transfer therapies to suppress self-specific or overaggressive immune responses that facilitate disease in autoimmune conditions and virus-associated pathologies.
Thanks to a New Scholar Award from the Ellison Medical Foundation, we are able to explore whether the immunoregulatory function of NK cells or the underlying molecular mechanisms of this activity are altered as a consequence of advanced age. We speculate that this activity of NK cells or the susceptibility of target cells is modulated by age in a manner that contributes to immune senescence in the elderly. Notably, advanced age is associated with an increased prevalence of cancer, reduced ability to combat infection, and a weak response against vaccines, including those against influenza.
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