LECTURE
Characterization of CD1d in mucosal immune function:
an immunotherapeutic target forin¯ammatory bowel disease
Richard S. Blumberg
Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA(Received for publication on September 11, 2000)

Abstract. In addition to the classical MHC class I and class II molecules, human intestinal epithelial
cells also express nonclassical MHC class I-like molecules on their cell surface. CD1d is a nonpolymorphic MHC-like molecule whose expression is mainly localized to the epithelial cells of thegastrointestinal tract. The biochemical structure of CD1d on intestinal epithelial cells (IECs) exists in
two forms: a 37-kD nonglycosylated, b2 -microglobulin (b2 M) independent and a 48-kD glycosylated,
b2 M dependent form. Immunolocalization studies suggest that the 37-kD nonglycosylated form ofCD1d is limited to the apical cell surface whereas the 48±50-kD glycosylated, b2 M dependent form ofCD1d is expressed both on the apical and the basolateral surfaces. The b2 M association with CD1dseems to be important in regulating the pattern of glycosylation and the localization of CD1d within thecell based upon studies of the structure of CD1d in a transfected model cell line and in polarized epithelial cell monolayers. The functional role of intestinal CD1d remains unknown. However, based
upon in vitro studies of the antigens presented by human CD1d and mouse CD1d, CD1d expressed on
IECs likely presents a very hydrophobic glycolipid molecule possibly from the cell wall of bacteria or
host cells. The processed-lipid antigen presented by CD1d may then involve a yet-to-be-identi®edsubpopulation of the resident, oligoclonal ab TCR CD8 intestinal intraepithelial lymphocyte (iIEL) T
cells. Subsequently, these T cells would be very important in regulating the local immune response by
producing cytokines and recruiting other immune modulating cells to destroy infected cells, regenerate
normal IECs, and possibly downregulate activated T cells to maintain mucosal integrity. (Keio J Med 50(1): 39±44, March 2001)
Key words: CD1d, mucosal immunity, in¯ammatory bowel disease, NK-T cells

a genetically susceptible host which is modi®ed by avariety of potential environmental factors leading to achronic in¯ammatory response that is manifest as tissue
injury and clinical symptoms.1 Although the genetic
basis for this disease is unknown, recent genome-widescans of humans with IBD have revealed potentiallycon®rmed loci on chromosomes 12 and 16.2 Although
the speci®c genetic elements that are associated with
IBD have not yet been identi®ed on these putative loci,based upon what is known to date, it can be predictedthat these genetic associations likely are involved in T
cell regulation and cytokine production, which impact

Introduction
Human in¯ammatory bowel disease (IBD) is a complex disorder of unknown origin that seems to represent the complex interactions between three factors
involving genetic susceptibility, environmental triggers
and immune dysregulation. More than 50 years of intense scienti®c investigation world wide, together withrecent rapid insights derived from immunologic studies
in humans and animal models, have converged in thefollowing, unifying hypothesis. IBD represents the dysregulated mucosal immune response to some antigen in

Presented at the 1174th Meeting of The Keio Medical Society in Tokyo, September 7, 2000.
Reprint requests to: Dr. Richard S. Blumberg, Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis
Street, Boston, MA 02115, USA, e-mail: rblumberg@partners.org. RSB was supported by grants from the National Institutes of Health(DK 44319, DK 51362 and DK 53056) and the Harvard Digestive Diseases Center.
39

40

Blumberg RS: CD1d in mucosal immune function

upon the mucosal immune response, and genes associated with mucosal barrier function and/or repair of a
disrupted barrier, which would impact on the access ofthe subepithelial immune system to antigens contained
within the lumen. Although the antigens that are putatively involved in the pathogenesis of IBD are unknown, a major breakthrough in our understanding of
this disease is the appreciation that the antigen is likely
derived from components contained within the normal
luminal microbiota. As such, IBD represents an inappropriate immune response to some component of thenormal microbiota in a genetically susceptible host.
Stated another way, in the genetically susceptible host,antigens from the normal microbiota may be perceived
as if they were a pathogen. Major support for such a
concept has come from a wide variety of animal models.3 A number of genetic perturbations in mice lead tochronic in¯ammation similar to that observed in human
IBD. In virtually all of these models that have beenstudied to date, which can be characterized as either
associated with perturbations of T cell regulation oralterations in mucosal barrier function and/or repair,colitis is observed only in the presence of the entericmicrobiota. Germ-free animals do not, in fact, develop
colitis in almost all of the animal models studied.3
Such notions of IBD pathogenesis focus signi®cantattention on the functions of the intestinal epithelial cell(IEC) which, together with the intestinal intraepithelial
lymphocyte (iIEL), are the ®rst cells to come in contact
with luminal antigens. These cells regulate transcytosisof macromolecules across the epithelium and paracellular permeability associated with barrier function
and function in immunosurveillance and local immunoregulation. This has led to the appreciation that the IEC
can function as an important component of the mucosaassociated lymphoid tissue. It is clear from numerous
studies that the IEC participates actively in innate immunity as manifest by its abilities to function in antimicrobial defense, produce in¯ammatory mediators andregulate leukocyte traf®c, can actively regulate barrier
function through the autocrine and paracrine functionof immune mediators (e.g. IL-10, TGF-b, IL-15) andparticipate in the immunosurveillance and immunoregulatory functions associated with adaptive immunity.4
MHC Class I-Related Molecules in Immune
Functions of Epithelium
One class of molecules that is prominently involvedin the immune functions of the human epithelium is the
major histocompatibility class I-related molecules. In
general, these molecules are characterized by a similar
structure that consists of a 43±48-kD heavy or a-chainthat is glycosylated and in non-covalent association withthe 12-kD b2-microglobulin (b2 M) molecule. In gen-eral, the MHC class I-related a-chain consists of three
extracellular domains, a1, a2 and a3, encoded by discrete exons. The MHC class I-related a-chains are type1 glycoproteins with a transmembrane region and ashort cytoplasmic tail. The MHC class I-related molecules can be divided into three types: the classical MHC
class I molecules which are encoded on the MHC locus
within human chromosome 6 (HLA-A, B and C), theMHC class I-related or class Ib molecules that are
encoded by genes linked to the MHC locus on humanchromosome 6 (HLA-E, F, G, H (Hfe)) and the MHC
class I-related gene chain A (MICA), and the MHC
class I-related or class Ib genes which are encoded outside of the MHC locus on other chromosomes (FcRn,zinc a-2 glycoprotein, MR1, CD1 and the protein C receptor).5 Whereas the classical class I molecules arecharacterized by signi®cant allelic diversity, a major
distinguishing feature of the so-called MHC class Ib
molecules, both MHC linked and unlinked, is their relative lack of allelic diversity, which causes them to beconsidered as non-polymorphic. The MHC class Ib
molecules can be thus distinguished from the classicalMHC class I molecules by their relative lack of polymorphism and their restricted cell and tissue distribution relative to the ubiquitously expressed classicalMHC class I molecules.
MHC class I-like molecules are prominently displayed on human IECs. These include CD1d, which is
encoded on chromosome 1 and is involved in the presentation of hydrophobic, glycolipid antigens to speci®csubsets of T cells, the neonatal Fc receptor for IgG(FcRn) which is encoded on chromosome 19 and whichfunctions in the bidirectional transport of human IgG
across the epithelial cell, the MICA which is encodedon chromosome 6 and is involved in the stress recognition of IECs by Vd1 T cells, HLA-H (Hfe) which is
encoded on chromosome 6 and involved in the regulation of iron transport across the epithelium, and HLAE which is encoded on chromosome 6 and involved in
the presentation of leader peptides from distinct typesof MHC class I molecules to killer inhibitory receptors(CD94/ NKG2) which is expressed on natural killer cells
and subsets of T cells and regulates their activity. The
remainder of this review will focus on the immunobiology of the CD1 molecules on the human intestinal
epithelium.
Human CD1
The human CD1 locus on chromosome 1 contains®ve genes: CD1a±e. These genes can be divided into
two types based upon nucleotide and deduced aminoacid sequence homologies.6 The so-called type 1 CD1gene products (CD1a, b, c and e) have been describedin humans, sheep and guinea pigs. The so-called type 2

Keio J Med 2001; 50 (1): 39±44

CD1 molecules includes a single member, CD1d, which
is observed in humans, rabbits, mice and rats. Notably,
the type 1 CD1 molecules are absent from rodents,
which only express the CD1d gene product. Interestingly, CD1 molecules in a given class are most homologous to members of that class such that human CD1d ismore homologous to rodent CD1d than it is to the human CD1a, b and c molecules. This fact, in particular,
suggests a conservation of function across the evolutionof species. The X-ray crystallographic structure ofCD1d has recently been solved.7 Similar to the classicalMHC class I molecules, the a1 and a2 domains of CD1d
forms a groove that is comprised of two a-helices and a¯oor composed of a series of b-pleated sheets. However, in contrast to the groove of the classical class I
molecule, which is wide and shallow and is competentto bind small 9±10 amino acid peptides for presentation
to CD8 T cells, the groove of CD1d is narrow anddeep, which is competent to bind large hydrophobic
molecules such as glycolipids. In fact, the electrostatic
surface charge of the CD1d-containing groove is neutral, consistent with this function in binding glycolipid
antigens. CD1d thus functions to bind glycolipid antigens for presentation to distinct subsets of T cells.
The glycolipid antigens that have been identi®ed todate to bind CD1d have similar structure and consist of
a-glycosylated phytosphingosines. Current models suggest that the lipid core of these glycolipids are boundwithin the two pockets of the CD1d groove with ahydrophilic cap formed by the sugar moiety facing out
into the aqueous milieu for recognition by the T cell
receptor (TCR) of distinct subsets of T cells.8 One
model glycolipid antigen that is capable of binding
CD1d and which has been quite useful in characterizing
the function of CD1d is a molecule called a-galactosylceramide (a-GalCer). This glycolipid was originallyisolated from marine sponge by Kirin Pharmaceuticals.9
This glycolipid consists of a ceramide moiety that ischaracterized by two acyl chains of 26 and 18 carbons inlength, respectively, in a-linkage with a galactose residue. Using a-galactosylceramide as a tool, it has beenshown that the lipid components of a-GalCer are boundto CD1d on an antigen-presenting cell and presented
to a distinct subset of T cells called Natural Killer-T(NK-T) cells which recognize the hydrophilic galactose
moiety (Fig. 1). NK-T cells are characterized by theiruse of an invariant TCR that is characterized as
Va14Ja281 in association with particular TCR b chains(Vb8) and the expression of certain natural killer cellmarkers such as CD161. Similar types of T cells havebeen identi®ed in humans.6 When activated, NK-T cells
rapidly express a TH0 phenotype and are therefore
thought to play an important role in the initiation andregulation of immune responses. It is important also torecognize that when an NK-T cell and CD1d-bearing

41

Fig. 1 CD1d on an antigen presenting cell (APC) presents agalactosylceramide to Natural Killer-T (NK-T) cells. [ref. 8]

antigen presenting cell (APC) communicate with eachother, activation occurs of not only the NK-T cell, butalso of the APC. The signals generated in the latter cell
type are, as of yet, poorly de®ned.
CD1d in the Human Intestine
A prominent tissue site for CD1d expression is theintestinal epithelium. We ®rst detected CD1d in mouseintestinal epithelial cells in 1990.10 Although our initialreport could not be con®rmed by others, more recently
it has, in fact, been con®rmed in rats and by us, inhumans and functionally in mice (vide infra).11,12 In
rats, CD1d transcription is quite low and limited to thecrypt epithelium with protein primarily detectable invillous epithelium.11 As noted, we have identi®ed
CD1d expression in human IECs, which, similar to rat
IECs, transcribe CD1d at very low levels. CD1d transcription in human intestinal epithelium has beenshown by us to be regulated by g-IFN13 and able toactivate peripheral blood T cells in IEC-peripheral
blood T cell co-cultures.14 Such activation is dependent
on CD1d and gp180, a carcinoembryonic antigenrelated molecule identi®ed by Mayer and colleagues on
IECs.15 CD1d expression on human IECs is polarized(Fig. 2). CD1d is expressed apical and predominantly
lateral as de®ned by confocal microscopy with CD1dspeci®c antibodies and selective cell surface biotinlabeling studies.16 Biochemically, CD1d is observed onhuman IECs in two forms: a 48-kD glycosylated form,
which is expressed in association with b2 M and distributed apical and basal, and a novel 37-kD form,
which is restricted apical, has a tendency to trimerize,
and is expressed without any evidence of N-linked carbohydrate side-chain modi®cations or association withb2 M.17,18 The 37-kD form appears to be derived froma novel post-translation modi®cation that involveshydroxylation of CD1d on proline residues due to aninteraction between CD1d and prolyl-4 hydroxylase
within the endoplasmic reticulum (unpublished data).

42

Blumberg RS: CD1d in mucosal immune function

Fig. 2 Biochemical Structure of CD1d on human intestinal epithelial
cells. CHOmature , mature N-linked carbohydrate; IEL, intraepithelial
lymphocyte; b2 M, b2 -microglobulin. [refs. 12, 16, 17, 18]

Functions of CD1d in Intestine
A major question that arises is, what is the functionof CD1d and how does it relate to the binding of glycolipid antigens and interactions with NK-T cells? One
hypothesis that arises from the biochemical data is thatCD1d functions in the processing and presentation of
glycolipid antigens, perhaps derived from the lumen, tolocal T cells. To begin to elucidate this, we haverecently investigated CD1d in a dextran sodium sulfate(DSS) colitis model. As is well known, DSS placed adlibidum in the drinking water induces colitis with nonin¯ammatory dropout of IECs as one of the earliestchanges suggesting that the primary event in this modelis at the level of the IEC. We therefore examined theeffects of a-GalCer and its non-functional analogue, amannosylceramide, in the DSS colitis model. Mice wereadministered 2.5% DSS ad libidum and either a-GalCeror a-ManCer at a dose of 100 mg/kg IP in wild-type
C57BL/6J, CD1d = or Rag-2 = mice. Mice weremonitored for daily weights, diarrhea, bleeding scoresand survival. These studies showed that wild-type miceare protected from colitis associated with DSS administration by a-GalCer but not a-ManCer.19 This protection was observed both clinically, as de®ned byevaluation of daily weight, diarrhea, bleeding scoresand survival, and histopathologically. In addition, theprotective effect of a-GalCer is dependent on the presence of CD1d and NK-T cells, since it was lost in the
CD1d = and Rag-2 = animals. In the absence ofCD1d, NK-T cells do not develop in the thymus andCD1d is not present on peripheral antigen presenting
cells. Similarly, in the absence of Rag-2, T cells, including NK-T cells, do not develop. Finally, the protective
effect of a-GalCer was likely mediated by activated
NK-T cells since it was lost with NK-T cell depletion by

antibody and gained with the transfer of a-GalCer, but
not a-ManCer, activated NK-T cells to Rag-2 = mice.
To begin to get at the mechanism(s) of this protection, the sites of localization of the parenterally administered a-GalCer were evaluated. a-GalCer labeledwith a ¯uorescent dye was injected parenterally intoeither wild-type or CD1d = mice. After four hours,colonic tissues were obtained and analyzed by confocal
microscopy. These studies showed that the green ¯uorescence, consistent with a-GalCer, was detectable predominantly in the surface epithelium of the mousecolon of the wild-type but not CD1d = animals, indicating that CD1d in this cellular location, was likely
binding the labeled lipid.19
We therefore focused our attention on the functionof CD1d in the IEC. We sought to model the effects ofCD1d ligation as might occur through glycolipid antigen binding or cross-linking of CD1d by a CD1drestricted T cell. To do so, we transfected the humanIEC line T84 by retroviral-mediated gene transfer witheither the wild-type CD1d cDNA or the CD1d DNA
that had been mutated to have a non-functional cytoplasmic tail.20 The CD1d cytoplasmic tail encodes atyrosine-based motif that consists of YXXZ; a wellknown sorting motif that is associated with tyrosine
phosphorylation characterized by tyrosine-amino acidamino acid-hydrophobic amino acid. By swapping thecytoplasmic tail of CD1d with the cytoplasmic tail of
CD1a that does not encode this motif, the cytoplasmic
tail of CD1d can be rendered non-functional. Thesestudies showed that antibody cross-linking of CD1d on
human IECs induced CD1d tyrosine phosphorylation
since phosphorylation of CD1d was observed in thewild-type but not the mutant. Moreover, substitution of
the CD1a cytoplasmic tail, which lacks the YXXZ motif, resulted in a dominant-negative phenotype in thateven phosphorylation of the endogenously expressed
CD1d was not observed. The tyrosine phosphorylation
triggered by CD1d speci®cally induced IL-10 production by IECs but not the production of pro-in¯ammatory cytokines such as IL-8 or TNF. This production of
IL-10 initiated by CD1d cross-linking was tyrosine
phosphorylation dependent since it was totally blocked
in a dose-dependent manner by genestein, a non-speci®c inhibitor of tyrosine kinase activity. Finally, theepithelial-derived IL-10 initiated by CD1d cross-linking
was able to attenuate g-interferon- (g-IFN) induced
permeability effects. We thus hypothesize that crosslinking of CD1d on an IEC leads to the production of
powerful barrier-enhancing and immunoregulatory
cytokines such as IL-10, which are able to abrogate orantagonize the proin¯ammatory and barrier disruptive
consequences of cytokines such as g-IFN (Fig. 3). Notably, g-IFN is a cytokine that is extremely important to
the pathogenesis of TH-1 responses often associatedKeio J Med 2001; 50 (1): 39±44

Fig. 3 Activation of CD1d on intestinal epithelial cells induces production of barrier promoting and down-regulatory cytokines. [refs. 19,
20]

with IBD and is a cytokine that is commonly expressedby most intraepithelial lymphocytes after activation.3
These data raised the question of how the activationof IEC regulatory functions by CD1d on the IEC mightoccur. There are two possibilities. One is that they are
NK-T cell dependent. In this model, the presentation of
glycolipid antigen to regional NK-T cells would lead tocross-linking of CD1d on the IEC and cross-linking of
the TCR/CD3 complex on the NK-T leading to activation of both cell types. Alternatively, it is possible that
activation of the IEC by glycolipid antigen may not require NK-T cells and thus be NK-T independent. In thismodel, CD1d is hypothesized to function in a novel
manner as a signaling receptor. We have therefore
begun to test these two hypotheses. In preliminary
studies, we have found that a-GalCer can directly block
the barrier effects of g-IFN using a transfected T84 cellline as a model system. In addition, we have observedthat human and mouse IECs can present a-GalCer, but
not a-ManCer, to model NK-T cell clones in a dosedependent fashion resulting in the production of cytokines such as IL-2 and IL-10. This presentation of aGalCer to human and mouse IECs to model NK-T
cells occurs in a CD1d-restricted fashion because it canbe blocked by anti-human CD1d and anti-mouse CD1d
speci®c monoclonal antibodies, respectively. Thesestudies suggest that activation of CD1d signaling
pathways on IECs may be both NK-T dependent andindependent.
Such studies also raised the question as to whether
NK-T cells can be detected among normal human intestinal intraepithelial lymphocytes. Human iIEL havebeen characterized in the past by us and others andfound to consist of an oligoclonally expanded popula-

43

tion that express on more than 95% of the lymphocytes
TCR-ab, CD8-ab, CD45RO, aEb7, CD-69, CD-101 and
BY55.21±22 Notably absent is the CD25 marker, indicative of the IL-2 receptor a-chain, and CD28, an important costimulatory molecule for most conventional T
cells. Such phenotypic characteristics suggest that iIEL
are memory cells in a novel state of activation that are
restricted to the basolateral surface of the epithelium
due to the expression of a unique constellation of
integrins for the recognition of a limited number ofantigens in the context of MHC class I-related molecules. With these considerations in mind, we haverecently stained normal human iIEL by multi-parameter ¯ow cytometry utilizing antibodies speci®c for theinvariant TCR-chain characteristic of CD1d-restricted
T cells, CD8 characteristic of iIEL, and CD161 characteristic of NK-T cells. Utilizing this methodologicalapproach, we have been able to reproducibly detect asmall subset of T cells within the human iIEL population consistent with the presence of NK-T cells. Specifically, T cells expressing the invariant TCR, CD8 andCD161 can be detected in this compartment. The
immunoregulatory functions of this small subset of cells
remains to be established. It is important to recognizethat the spectrum of CD1d-responsive T cells is increasingly expanding to include not only the classical
NK-T cell, but also other T cell subsets that do not express either the characteristic TCR-a or b chain of thiscell type.8 Thus, where human IEL ®t into this rubric is
unknown.
Summary
In summary, CD1d is expressed in a polarized manner in biochemically distinct forms on human and rodent IECs. Functional studies in rodents would suggestthat activation of CD1d-NK-T-related pathways leads
to the generation of immunoregulatory factors that areboth anti-in¯ammatory and barrier-enhancing; characteristics that would be quite bene®cial to the perturbations associated with IBD. Our studies would suggestthat activation of CD1d on IECs in either an NK-Tdependent or -independent fashion leads to the productionof cytokines such as IL-10, which can directly regulate
IEC barrier function in an autocrine manner. It is therefore possible that glycolipid antigens, perhaps derived
from luminal microbial antigens, may either directly
stimulate CD1d on IECs or indirectly stimulate IECs
through presentation of these glycolipid antigens to local
CD1d-restricted T cells such as the NK-T cell. Thesestudies further suggest that NK-T cells may be a novel
type of immunoregulatory cell relevant to IBD pathogenesis.23 How these insights relate to immunotherapeutic approaches in IBD remains to be established.
However, it is becoming increasingly clear that ration-

44
Table 1

Blumberg RS: CD1d in mucosal immune function
In¯ammatory Bowel Disease: Rationalizing Therapy [adapted from ref. 1]

TargetMechanisms

Antigen
T Cell/APC Interactions
Cytokines & Membrane Receptors
Cellular Recruitment
In¯ammatory Mediators
Epithelial Repair & Healing

Therapeutic

Eliminate and/or prevent uptake of pathogenic
bacterial strain and/or antigens
Block excess costimulation
Block pro-in¯ammatory & increase antiin¯ammatory cytokines
Block T cell homing/endothelial cell addressins
Block activity of proteases & ROM
Increase epithelial proliferation & barrier function

alizing IBD therapy around the sequence of immunologic events associated with IBD pathogenesis is extremely important (Table 1).
References
1. Blumberg RS, Strober WS: In¯ammatory Bowel Disease. J Am
Med Assoc 2000; In Press
2. Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee
JC, Beaugerie L, Naom I, Dupas JL, Van Gossum A, Orholm M,
et al.: Mapping of a susceptibility locus for Crohn's disease on
chromosome 16. Nature 1996; 379: 821±823
3. Blumberg RS, Saubermann LJ, Strober W: Animal models of
mucosal in¯ammation and their relation to human in¯ammatory
bowel disease. Curr Opin Immunol 1999; 11: 648±656
4. Christ AD, Blumberg RS: The intestinal epithelial cell: immunological aspects. Springer Semin Immunopathol 1997; 18: 449±
461
5. Blumberg RS: Current concepts in mucosal immunity. II. One
size ®ts all: nonclassical MHC molecules ful®ll multiple roles inepithelial cell function. Am J Physiol 1998; 274(2 Pt 1): G227±
G231
6. Porcelli SA, Modlin RL: The CD1 system: antigen-presenting
molecules for T cell recognition of lipids and glycolipids. Annu
Rev Immunol 1999; 17: 297±329
7. Zeng Z, Castano AR, Segelke BW, Stura EA, Peterson PA,
Wilson IA: Crystal structure of mouse CD1: an MHC-like foldwith a large hydrophobic binding groove. Science 1997; 277:
339±345
8. Naidenko OV, Koezuka Y, Kronenberg M: CD1-mediated antigen presentation of glycosphingolipids. Microbes Infect 2000; 2:
621±631
9. Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y,
Koseki H, Kanno M, Taniguchi M: Requirement for Valpha14
NKT cells in IL-12-mediated rejection of tumors. Science 1997;
278: 1623±1626
10. Bleicher PA, Balk SP, Hagen SJ, Blumberg RS, Flotte TJ, Terhorst C: Expression of murine CD1 on gastrointestinal epithelium. Science 1990; 250: 679±682
11. Kasai K, Matsuura A, Kikuchi K, Hashimoto Y, Ichimiya S:
Localization of rat CD1 transcripts and protein in rat tissues ± ananalysis of rat CD1 expression by in situ hybridization andimmunohistochemistry. Clin Exp Immunol 1997; 109: 317±322

Antibiotic or Probiotic, therapeutic vaccine,increase epithelial cell barrier function
Anti-CD80/86, Anti-CD40L
Anti-TNF, Anti-IL-12, IL-10, TGF-b, Blockade
of NF-kB or activate regulatory cells (NK-T,
Tr1, TH 3)
Anti-a4b7, anti-MadCAM-1
Metalloprotease inhibitors, Antioxidants
IL-11, Trefoil Factors, KGF

12. Blumberg RS, Terhorst C, Bleicher P, McDermott FV, Allan
CH, Landau SB, Trier JS, Balk SP: Expression of a nonpolymorphic MHC class I-like molecule, CD1D, by human intestinal epithelial cells. J Immunol 1991; 147: 2518±2524
13. Colgan SP, Morales VM, Madara JL, Polischuk JE, Balk SP,
Blumberg RS: IFN-gamma modulates CD1d surface expression
on intestinal epithelia. Am J Physiol 1996; 271(1 PT 1): C276±
C283
14. Panja A, Blumberg RS, Balk SP, Mayer L: CD1d is involved in T
cell-intestinal epithelial cell interactions. J Exp Med 1993; 178:1115±1119
15. Campbell NA, Kim HS, Blumberg RS, Mayer L: The nonclassical class I molecule CD1d associates with the novel CD8
ligand gp180 on intestinal epithelial cells. J Biol Chem 1999; 274:
26259±26265
16. Somnay-Wadgaonkar K, Nusrat A, Kim HS, Canchis WP, Balk
SP, Colgan SP, Blumberg RS: Immunolocalization of CD1d inhuman intestinal epithelial cells and identi®cation of a beta2microglobulin-associated form. Int Immunol 1999; 11: 383±392
17. Kim HS, Garcia J, Exley M, Johnson KW, Balk SP, Blumberg
RS: Biochemical characterization of CD1d expression in the absence of beta2-microglobulin. J Biol Chem 1999; 274: 9289±9295
18. Balk SP, Burke S, Polischuk JE, Frantz ME, Yang L, Porcelli S,
Colgan SP, Blumberg RS: Beta 2-microglobulin-independent
MHC class Ib molecule expressed by human intestinal epithelium. Science 1994; 265: 259±262
19. Saubermann LJ, Beck P, De Jong YP, Pitman RS, Ryan MS,
Kim HS, Exley M, Snapper S, Balk SP, Hagen SJ, Kanauchi O,
Motoki K, Sakai T, Terhorst C, Koezuka Y, Podolsky DK,
Blumberg RS: Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection
against colitis in mice. Gastroenterology 2000; 119: 119±128
20. Colgan SP, Hershberg RM, Furuta GT, Blumberg RS: Ligationof intestinal epithelial CD1d induces bioactive IL-10: critical roleof the cytoplasmic tail in autocrine signaling. Proc Natl Acad Sci
USA 1999; 96: 13938±13943
21. Probert CS, Aitken EW, Saubermann LJ, Balk SP, Blumberg
RS: T-cell receptor usage in the intestine. Chem Immunol 1998;
71: 27±39
22. Balk SP, Ebert EC, Blumenthal RL, McDermott FV, Wucherpfennig KW, Landau SB, Blumberg RS: Oligoclonal expansion
and CD1 recognition by human intestinal intraepithelial lymphocytes. Science 1991; 253: 1411±1415
23. Sakaguchi S: Regulatory T cells: key controllers of immunologic
self-tolerance. Cell 2000; 101: 455±458