Waggoner Lab

  • Current Projects

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    + Determination of the antigenic nature of the targets of NK cell immunoregulatory activity

    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.

    + Ascertain the triggers of NK cell immunoregulation

    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 in the induction of immunological memory after vaccination or acute infection

    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.

    + NK cell immunoregulation and autoimmune disease

    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.

    + NK cell-based therapies for chronic infection and autoimmune disease

    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.

    + Age-associated changes in NK cell regulatory capacity and related immune dysfunction

    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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    Figure 1. Pathogenesis of lymphocytic choriomeningitis virus (LCMV) infection is related to the size of virus inoculum and the presence of NK cells. A balance exists between the amount of virus replication and the number of effective virus-specific T cells, which dictates both virus elimination and immune-mediated tissue damage (red zone on sliding scale). After inoculation with a high dose of virus, the virus-specific T cells become functionally impaired (exhaust) resulting in sustained high levels of this non-cytopathic virus. Thus, mice survive with a persistent infection but relatively little disease. At a very low virus dose, the immune response is strong and virus is cleared, resulting in minimal disease as a consequence of resolution of inflammation. An intermediate virus inoculum drives prolonged virus replication in the context of sustained immune function and inflammation, which results in fatal immune pathology. NK cells are dispensable for very early control of LCMV infection prior to the development of adaptive immune responses. Nonetheless, depletion of NK cells resulted in an enhanced T cell response, which alters the balance between virus and immunity, thereby modulating the dose at which immune pathology occurs. This suggests that NK cells play a vital regulatory role in the immune response to LCMV.
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    Figure 2. NK cells regulate the T cell response by acting upon CD4 T cells. During infection with a number of viruses, NK cells were stimulated to kill activated CD4 T cells at early time points of infection. In this manner, NK cells could regulate the overall T cell response by reducing the CD4 T cell help required to sustain CD8 T cell function in the context of persistent levels of replicating virus. This contributes to an accumulation of excess viral antigen that can exhaust both CD4 and CD8 T cells, thereby facilitating viral persistence.