Areas of Interest
An effective immune response depends on the large-scale, but
carefully regulated, movement of cells within and between
lymphoid and peripheral tissues. Secondary lymphoid organ
structure is the underlying regulator of immune responses and is
responsible for promoting interactions between cells as well as
between cells and extracellular matrix. In recent years, our
understanding of events in secondary lymphoid tissues has been
advanced by the use of multiphoton microscopy to visualize
lymphocyte movement. Nevertheless, much remains to be revealed
about the microanatomy of antigen-specific primary and memory
CD8 T cell responses, with relatively limited data currently
available from in situ visualization of endogenous CD8 T cell
responses. My recent results have helped illuminate the
landscape under which the endogenous CD8 T cell immune response
occurs (Khanna, et.al. Science, 2007). These findings have set
the stage for in situ identification of the cell types and other
factors that control the processes driving each anatomical phase
of the immune response to infection.
In my lab we will combine well established research methods with
the novel tools that I have recently developed, which include: (i)
whole mount confocal microscopy techniques using in situ MHC
class I tetramer staining to allow visualization of endogenous
antigen-specific CD8 T cells in virtually any tissue. This
powerful method increases detection sensitivity and preserves
the functional/physical anatomy of organs being studied. (ii) A
new transgenic mouse (CD11c-mCherry) that expresses a red
fluorescent protein (RFP) variant called mCherry under control
of the CD11c promoter to allow visualization of dendritic cells
(DC) in vivo and (iii) multi-photon imaging in vivo imaging. I
have just established a state of the art two photon imaging
system in my lab. It is a custom built Prairie microscope with 4
channel detection fitted with a Specter Physics, MaiTai DeepSee
two photon laser.
Department of Immunology
Lab Rotation Projects
Investigate the role of sphingosine-1-phosphate (S1P)
receptors in the local migration and localization of CD8 T cells
and DC after infection: S1P receptors play a role in
migration and retention of T cells in primary and secondary
lymphoid organs. In collaboration with Tim Hla’s lab we will use
novel mouse models to determine the role of S1P receptors in T
cell and DC homing and migration under normal conditions as well
as during infection. We will also employ dynamic intravital two
photon microscopy to visualize the role of S1P receptors in T
cell and DC activation and migration after infection.
Visualize the dynamics of CD8 T cell immune response during
latent herpesvirus infections: Herpesvirus infections are
considerably widespread, where the virus establishes a life long
infection in its host even in the presence of concomitant
immunity. Understanding the co-existence of latent virus in the
presence of an active immune system is an important biological
problem that offers a fascinating model for studying T cell
immunobiology. Following MCMV infection certain immunodominant
epitope (during lytic phase of MCMV infection) specific CD8 T
cells contract and continue to “deflate” during the latent phase
of the infection. However, other epitope specific CD8 T cells
continue to gradually expand throughout the life of the host
long after latency is established. The mechanisms that
contribute to this intriguing interplay of “deflationary” vs.
“inflationary” anti-viral CD8 T cell responses are poorly
understood. Thus, one of my goals will focus on understanding
the dynamics of the immune system during latent herpesvirus
infections.
Investigate the role of pregnane X receptor (PXR; orphan
nuclear receptor) in host defense and the maintenance of
homeostasis against gastrointestinal bacterial infections in
vivo: The mucosal surface of the gut is a specialized organ
defending against entry of toxins and bacteria. This component
of “innate immunity” utilizes pattern recognition receptors
(also called PRRs), like the TLRs, the first line of defense
against foreign challenge. Although recent reports have
identified potential mechanisms that mediate immune homeostasis
during steady state conditions, our understanding of the
components that regulate host defense against infections in the
intestinal mucosa remains poor. This is especially true with
respect to xenobiotic receptors, including Pregnane X-Receptor (PXR).
PXR is highly expressed in the intestinal epithelial cells and
have recently been shown to be important in maintaining immune
homeostasis in inflammatory bowel disease. Our preliminary data
shows that PXR can regulate components of the innate immune
system and thus is likely to play an important role in
regulating immunity against intestinal pathogenic infections.
Two Photon confocal microscopy: Many elegant studies
recently have pioneered the use of two photon microscopy to
visualize T cell activation and migration in an intact mouse or
in tissue explants. My lab is equipped with a state of the art
two photon imaging system to perform intravital dynamic imaging
of immune cells in vivo. My lab uses novel mice models to
visualize the role of various proteins including S1P1R in T cell
and dendritic cell activation and migration. In addition, my lab
will focus on imaging the onset of a primary as well as a
secondary immune response to viral and bacterial infection. To
this end, fluorescent viruses and bacteria will be used to
visualize the interplay between the antigen presenting cells and
the responding antigen specific T cells in live animals and in
explanted secondary lymphoid organs.
Publications
Knickelbein, J.E., Khanna, K.M., Yee, M.B., Baty, C.J.,
Kinchington, P.R., and Hendricks, R.L. (2008) Noncytotoxic Lytic
Granule-Mediated CD8+ T Cell Inhibition of HSV-1 Reactivation
from Neuronal Latency. Science. 322: 268-271.
Khanna, K.M., Aguila, C., Redman, R., Lefrançois, L., and Cauley,
L.S. (2008) In situimaging reveals different responses by naïve
and memory CD8 T cells to late antigen presentation by lymph
node DC after influenza virus infection. Eur.J.Immunol. (In
Press).
Obar J.O., Khanna, K.M., and Lefrancois, L. (2008) Endogenous
naïve CD8 T cell precursor frequency regulates primary and
memory responses to infection. Immunity. 28: 859-869.
Khanna. KM. and Lefrancois. L. Geography and plumbing control
the T cell response to infection. (2008) Immunology and Cell
Biology.86: 416-422.
Khanna, K.M., Vella, A.T., McSorley, S.J., Datta, S.K., and
Lefrançois, L. (2008) T cell and antigen-presenting cell
dynamics in situ control the outcome of vaccination (submitted).
Khanna, K.M., McNamara, J.T., and Lefrançois. L. (2007) In situ
imaging of the edogenous CD8 T cell response to infection.
Science. 318: 116-120.
Turner, D.L., Cauley, L.S., Khanna, K.M., Lefrancois, L. (2007)
Persistent antigen presentation after acute vesicular stomatitis
virus infection. J. Virol. 81: 2039-2046.
Sheridan, B.S., Khanna, K.M., Frank, G.M., Hendricks, R.L.
(2006) Latent Virus influences the generation and maintenance of
CD8+ T cell memory. J Immunol. 177: 8356-8364.
Cose. S, Brammer, C., Khanna, K.M., Masopust, D., Lefrançois, L.
(2006) Evidence that a significant number of naive T cells enter
non-lymphoid organs as part of a normal migratory pathway. Eur.
J. Immunol. 36: 1423-1433.
Khanna, K.M., Lepisto, A.J., and Hendricks. R.L. (2004) Immunity
to latent viral infection: many skirmishes but few fatalities.
Trends. Immunol. 25: 230-234.
Khanna, K.M., Lepisto, A.J, Decman, V, and Hendricks, R.L.
(2004) Immune control of herpes simplex virus during latency.
Curr.Opin.Immunol. 16: 463-469.
Khanna K.M., Bonneau R.H., Kinchington P.R., and Hendricks R.L.
(2003) Herpes simplex virus glycoprotein B-specific memory CD8+
T cells are activated and retained in latently infected sensory
ganglia and can regulate viral latency. Immunity. 18: 593-606.
Niehaus G.D., Ervin E., Patel A., Khanna K., Vanek V.W., Fagan
D.L. (2002) Circadian variation in cell-adhesion molecule
expression by normal human leukocytes. Can. J. Physiol.
Pharmacol. 80: 935-940.
Liu T, Khanna K.M., Carriere B.N., and Hendricks R.L. (2001)
Gamma Interferon can prevent herpes simplex virus type 1
reactivation from latency in sensory neurons. J. Virol. 75:
11178-11184.
Liu T, Khanna K.M., Chen X.P., Fink D.J., and Hendricks R.L.
(2000) CD8+ T cells can block herpes simplex virus type 1
(HSV-1) reactivation from latency in sensory neurons. J.Exp.Med.
191: 1459-1466. |
