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THE STRUCTURE AND FUNCTION OF HLA-E
CA OCALLAGHAN, VM BRAUD, DSJ ALLEN, L LANIER, AJ
MCMICHAEL AND JI BELL
Molecular Immunology Group, Institute of Molecular Medicine,
University of Oxford. John Radcliffe Hospital. Oxford OX3 9DS.
The classical HLA molecules, HLA-A, HLA-B and HLA-C are
highly polymorphic and play a key role in T cell recognition. In
contrast, HLA-E, a non classical HLA molecule. is highly conserved
and non polymorphic suggesting an important and different
function. We have shown that HLA-E plays a central role in natural
killer cell recognition. Natural killer cells are potent immune cells
which destroy a wide range of targets cells including tumour and
infected cells.
HLA-E is expressed in the endoplasmic reticulum where it binds a
peptide fragment derived from the HLA-A, -B and -C moleculec.
This stabilises HLA-E which then migrates to the cell curface.
However, if the peptide fragment is not present, HLA-E is degraded
in the endoplasmic reticulum and does not reach the cell surface.
The crystal structure of HLA-E shows that it has evolved to bind
with high specificity to a characteristic signal sequence peptide
which is common to HLA-A, -B and -C molecules (Molecular Cell 1
53 1-541). This specificity is mediated by a number of novel
structural mechanisms.
Tetrameric recombinant HLA-E molecules were used to show that
HLA-E interacts with the CD94MKG2 C-lectin type receptors on
natural killer cells (Nature
795-799).This interaction inhibits
natural killer lysic of the cell displaying HLA-E and conversely any
cell without HLA-E on its surface is destroyed by natural killer cells.
In virus infected or tunmur cells there is often inhibition of HLA -A,
-Bor -C synthesis or interference with the normal antigen peptide
processing pathways. When this happens. HLA-E cannot form a
stable complex and cannot reach the cell surface leaving the tuniour
or infected cell vulnerable to natural killer cell lysis
We have used recornbinant protein technology to define the
structure and function of HLA-E. HLA-E i i recognised by natural
killer cells and its presence at the cell surface confirms the integrity
of key intracellular processes and inhibits natural killer cell lysis.
Y2
THE ROLE OF LEPTIN IN THE CELL-MEDIATED
IMMUNE RESPONSE AND T LYMPHOCYTE
DEVELOPMENT
GM LORD, JK HOWARD', G MATARESE, RJ BAKER, SR
BLOOM' and RI LECHLER
Imperial College School of Medicine, Departments of
Immunology and Endocrinology', Hammersmith Hospital, London
W12 O N N , England
Starvation is associated with cell-mediated immune dysfunction.
The adipocyte-derived hormone leptin reflects nutritional status
in that its circulating levels are proportional to fat mass and are
lowered rapidly by fasting. We show that the leptin receptor is
present on CD4+ T cells and that leptin differentiallyregulates the
proliferation of naive and memory T cells. Additionally,it favours
Thl and suppresses Th2 cytokine production. In vivo, prevention
of the fasting-induced fall in endogenous leptin with exogenous
administration completely reverses the immune dysfunction
associated with starvation in mice.
Furthermore, thymic atrophy has been recognised as a prominent
feature of malnutrition in animals and man. Acute starvation in
normal mice causes a dramatic reduction in the total thymocyte
count, predominantly due to diminution of the CD4+/CD8+
thymocyte subpopulation. In starved mice, preventing the fall in
leptin levels by administration of exogenous leptin is able to
protect mice from these profound thymic atrophic changes. A
similar defect in thymocyte maturation and survival is seen in the
leptin deficient obhb mouse, which is corrected by administration
of exogenousleptin. We demonstratethat leptin prevents apoptosis
of immature thymocytes in vitro and in vivo, thus providing an
explanation for these observations.
We therefore propose that leptin is a key link between nutritional
status and the immune system and provides a molecular
mechanism to explain the immune dysfimction observed in
starvation.
Y3 THE
ORGANISATION AND REORGANISATION OF HUMAN
SWALLOWING MOTOR CORTEX: IMPLICATIONS FOR RECOVERY AFTER
STROKE
S HAMDY'1,2, J C ROTHWELL', Q AZIT?, and D G THOMPSONQ
'MRC Human Movement and Balance Unit, Institute of Neurology, London, WC1
3BG, 2Universily Department of Gastroenterology, Hope Hospital Salford, M6
EHD, UK
BackgroundAlms: Dysphagia after stroke is a common problem and yet our
understanding of this devastating complication remains poor. The aim of this
study was to explore the central neural control of human swallowing, in order to
determine the basis for the development and recovery of stroke induced
dysphagia. Methods: Cortical projections to human swallowing musculature
were investigated both in health and after stroke using transcranial magnetic
stimulation (TMS).The cortically evoked EMG potentials were recorded from ring
electmdes housed within a swallowed catheter, enabling muscles of the mouth,
pharynx and oesophagus to be mapped and their senson-motor interactions
examined. In addition, the cerebral loci pmcessing swallowing were identied
using positron emission tomography (PET). Results: TMS mapping of healthy
swallowing motor cortex demonstrated a somatotopic organisation, with oral
muscles lateral and pharynx and oesophagus medial. For most subjects, one or
other hemisphere had greater representation, irrespective of handedness. This
motor cortex asymmetry was substantiated with PET, which also demonstrated
that swallowing recruits additional regions including insula, temporopolar cortex,
cerebellum and brainstem,each with differing degrees of lateralisation. Following
short-term (10mins)sensory conditioning of the pharynx, differential long-term
(3Omins)changes in the excitabilityof swallowing motor cortex were induced, with
facilitation of pharyngeal but inhibition oesophageal interneurons. Following
stroke, stimulation of affected motor cortex produced l i e or no response in either
dysphagic or nondysphagic patients, while stimulation of unaffected motor cortex
evoked larger responses in the nondysphagic than in the dysphagic patients.
This suggests that the size of the intact motor projection to pharynx determines
the presence of dysphagia. Longitudinal studies in dysphagic patients who
recovered swallowing demonstrated an increased pharyngeal representation in
unaffected motor cortex over time with little change in affected motor cortex.
Conclusions: Swallowing motor cortex is somatotopically but asymmetrically
organised and its topography can be remodelled by sensory input. This cortical
asymmetry helps explain the Occurrence of dysphagia after stroke, whereas
swallowing recovery relates to intact hemisphere reorganisation. The latter
observation may be important in targeting therapies, such as sensory stimulation.
towards accelerating the recovery process.
Y4 THE NRAMP HOMOLOGUE ENCODED BY MYCOBACTWUM
TUBERCULOSIS IS A PH-DEPENDENT DIVALENT CATION
TRANSPORTER
D.AGRANOFF', 1. MONAHAN', I. MANGAN?, P. BUTCHER' AND S.
KRISHNA'
'Dept. of Infectious Diseases. 'Dept. of Microbiology,SI George's Hoepital
Medical School, London SW 17 ORE
Mammalian Natural Resistance Associated Macrophage Pmtein
(Nramp) hodogues are important determinants of susceptibility to
infection by diverse inhaallular pathogens including mycobacteria
[Skamene E. et al Ann. Rev. Med. (1998),4!227S~.Functional studies
have shown that the Nramp family of proteins transports divalent cations
such as Feh. Mn", Zn'* and Cuh [Gunshin H. ef a/ Nature (1997). 388:4824881.Several intraccllular pathogensalso encode Nramp homologues which
have not been functionally characterized [Agrand D. er a1 Md. Micmbiol.
(1998). 28:4a)412]. We have identified an Nramp homdogue in
Mycobacterium Yhrculosb and M.bovb (BCG) (designated 'Mramp') and
studied its function. Mmmp encodes a 428 amino acid integral mcmbranc
protein containing sequence motifs which are similar to those of eukarydc
members of thc Nramp family. By expressing h
p in Xenopus o a y t e s
we demonstrate that it behaves 08 a pH-sensitive transporter of Fe" and ah'.
with activity did to an extracellular pH range 5.56.5. Excess