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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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