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CUTTING EDGE |
ß+ CD8+ T Cells Are Found in Intestinal Intraepithelial Lymphocytes of Mice That Lack Classical MHC Class I Molecules1
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ intestinal intraepithelial lymphocytes
(IEL) can express either the typical CD8ß heterodimer or an
unusual CD8 homodimer. Both types of
CD8+ IEL require class I molecules for
their differentiation, since they are absent in
ß2m-/- mice. To gain insight into the role
of class I molecules in forming TCRß+
CD8+ IEL populations, we have analyzed
the IEL in mice deficient for either TAP, ß2m, CD1, or K
and D. We find that K-/-D-/- mice have
TCRß+
CD8+ IEL, although they are
deficient for TCRß+
CD8ß+ cells. This indicates that at
least some TCRß+
CD8+ IEL require only nonclassical
class I molecules for their development. Surprisingly, the
TCRß+
CD8+ IEL are significantly
increased in K-/-D-/- mice, suggesting a
complex interaction between CD8+ IEL and class I molecules
that might include direct or indirect negative regulation by K
and D, as well as positive effects mediated by nonclassical class I
molecules. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ CD8 single-positive intraepithelial
lymphocytes (IEL)3.
These can be subdivided into approximately one third that express the
conventional form of CD8, a CD8ß heterodimer, and those that
express a CD8 homodimer, a type of CD8 found almost exclusively
in IEL. Relatively minor populations of
TCRß+ IEL also are
CD4-, CD8- double
negative (DN), CD4+, or
CD4+, CD8+ double
positive (DP). The expression of CD8 by most IEL suggests that these cells recognize Ags presented by class I molecules, and, although there is evidence for this in some cases (1), the specificity of most IEL remains unknown. Class I molecules in mice include the MHC-encoded classical or class Ia proteins, H2-K, D, and L, the nonclassical or class Ib molecules encoded by genes in the Q, T, and M regions of the MHC, and nonclassical class I molecules encoded by genes outside the MHC, such as CD1. Interestingly, several nonclassical class I molecules, including CD1 and the thymus leukemia (TL) Ag, have been reported to be highly expressed by intestinal epithelial cells (2, 3, 4).
The role of MHC class I in the selection of CD8+
intestinal IEL was first addressed using
ß2m-/- mice, which have
a greatly reduced expression of all classical and nonclassical class I
molecules (5, 6, 7, 8). These studies indicated that
TCRß+ CD8 single-positive cells were greatly
decreased, suggesting a role for MHC class I molecules in the
development of TCRß+
CD8+ T cells, regardless of the form of the CD8
molecule they express. By contrast, the predominantly
CD8+ T cells expressing a 
TCR were
found in equal number in
ß2m-/- and control
animals, demonstrating that this population did not require MHC class I
molecules for its development (5).
TAP-/- and
ß2m-/- mice appear
similar with regard to both their decreased levels of MHC class Ia
expression and their numbers of CD8+ T cells
present in the spleen and lymph nodes. Surface expression of several
class Ib molecules, however, including the TL Ag and CD1 molecules
expressed in the intestine, is independent of a functional TAP molecule
(9, 10, 11, 12). Interestingly, compared with
ß2m-/- mice,
TAP-/- animals were reported to have increased
numbers of TCRß+
CD8ß+,
TCRß+
CD8+, and
TCRß+ DP small intestine IEL (7, 8), although the numbers of TCRß+ CD8
single-positive IEL are reduced in TAP-/- when
compared with wild-type mice. This led to the hypothesis that some
TCRß+ CD8 single-positive IEL are selected
by TAP-independent nonclassical class I molecules. The interpretation
of these results is complicated by the fact that the TAP mutation
causes a slightly less severe decrease in the level of class Ia
molecule expression than does the lack of ß2m
(13). Because neither
ß2m-/- nor
TAP-/- mice have complete deficits for K and D
expression, neither mutant strain provides an ideal model for
determining the degree to which CD8+ IEL are
dependent upon classical class I molecules. Here we have taken
advantage of several more recently generated strains of mice, including
mice that are deficient for functional K and D
genes (14, 15). No classical MHC class I molecules are
detectable in these animals, although ß2m and
the nonclassical MHC class Ib molecules examined so far are expressed
normally (15). The results derived from these mice
demonstrate surprising differences in the dependence of different
subpopulations of CD8+ IEL upon classical and
nonclassical class I molecules.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and 129 strains of mice were obtained from The Jackson Laboratory (Bar Harbor, ME). (C57BL/6 x 129)F1 mice were bred from the parental strains in the vivarium at the La Jolla Institute of Allergy and Immunology. Kb-/-Db-/- mice have been described previously (14, 15) and were kindly provided by Dr. J. Forman (University of Texas Southwestern Medical Center, Dallas, TX) with permission of Dr. F. Lemonnier (Institut Pasteur, Paris). The mice were back-crossed three times onto the C57BL/6 background before use. TAP 1-/- mice on the mixed C57BL/6 x 129 background were bred from stock originally obtained from Dr. L. Van Kaer (Vanderbilt University, Nashville, TN). ß2m-/- mice on the C57BL/6 x 129 background were bred from stock obtained from Dr. B. Koller (University of North Carolina, Chapel Hill, NC). Dr. M. J. Grusby (Harvard Medical School, Boston) kindly provided mice lacking both the CD1.1 and CD1.2 genes (CD1-/-) on the mixed BALB/c x 129 background. Mice 6 to 12 wk old of both sexes were used, except for CD1-/- mice, which were analyzed at 10 mo. All mice were housed under specific pathogen-free conditions in the La Jolla Institute for Allergy and Immunology vivarium.
Flow cytometry
IEL were prepared as described previously (16). IEL
or other lymphocytes were suspended in buffer comprised of PBS (pH 7.4)
containing 2% (w/v) BSA and 0.02% NaN3 (w/v).
After blocking with the 2.4G2 anti-FcR mAb (except for the CD16
staining), the cells were stained at 4°C for 30 min with the labeled
mAb, then washed and analyzed on a Becton Dickinson FACScan (San Jose,
CA) 440 flow cytometer. Lymphocytes were enumerated out of the
heterogeneous cell population obtained following IEL preparation by
electronic gating, as determined by analysis of FSC and SSC.
The following mAbs were used for phenotypic analysis of lymphocytes:
PE- or CyChrome-labeled anti-TCR ß clone H57-597, FITC-labeled
anti-TCR clone GL-3, FITC-labeled anti-CD4 clone GK1.5,
FITC- or PE-labeled anti-CD8 clone 53-6.7, PE-labeled
anti-CD8ß clone 53-5.8, FITC-labeled anti-CD5 clone 53-7.3,
FITC-labeled anti-CD103 (integrin IEL
chain or E) clone M290, PE-labeled
anti-CD122 (IL2R ß-chain) clone TM-b1, PE-labeled anti-CD44
clone IM7, PE-labeled anti-CD16 clone 2.4G2,
biotinylated-anti-CD28, and biotinylated-anti-CD90.2 (Thy1.2)
clone 53-2.1. All Abs were purchased from PharMingen (San Diego, CA).
Stainings involving biotinylated Abs were revealed using
streptavidin-tri-color conjugate (Caltag, Burlingame, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ CD8ß+ IEL are absent in
Kb-/-Db-/- mice
IEL populations from different class I-deficient animals were
analyzed to evaluate the respective role of MHC class Ia and class Ib
molecules in the development of TCRß+
CD8+ IEL. In Fig. 1
is shown representative flow cytometry analysis of IEL populations
found in control mice (C57BL/6), three class I-deficient strains,
including ß2m-/- mice,
TAP-/- mice, and
Kb-/-Db-/- mice, as
well as CD1-/- mice. In the absence of the
ß2m molecule, the percentage of
TCRß+ cells in the total IEL population is
severely decreased (11 ± 2.5% TCRß+
in ß2m-/- mice
(n = 5) vs 43.4 ± 10.5% in C57BL/6 mice
(n = 9)). The decrease is less severe in TAP-deficient
animals (27.9 ± 5.2% (n = 6)) and absent in
Kb-/-Db-/- (47.3
± 11.7% (n = 10)). By contrast, the
TCRß+ CD8+ population
is markedly decreased in the spleen (<5% vs 30% in C57BL/6) and
lymph nodes of the three MHC class Ia knockout mice, but not in
CD1-/- mice (data not shown).
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ß+ populations are detected, DN,
CD4+CD8+ (DP),
CD4+ single positive,
CD8ß+ single positive, and
CD8+ single positive, as previously
reported (17, 18). While TAP-/-
animals contain the same five populations, in both
ß2m-/- and
Kb-/-Db-/- mice, the
TCRß+ CD8ß+ cells
are missing (Fig. 1
). The relative contribution or percentage of the
different TCR ß+ populations among total IEL
was evaluated by flow cytometry (Fig. 2).
No significant difference can be detected for the
TCRß+ CD4 single positive and DN cells
between the three class Ia-deficient animals (Fig. 2). A significant
percentage of CD8ß+ IEL can still be
detected in TAP-/- mice (2.2 ± 0.9%) but
not in ß2m-/- mice
(0.2 ± 0.2%), although this population is greatly decreased when
compared with C57BL/6 mice (15.9 ± 6.3%). The MHC class
Ia-deficient Kb-/-Db-/-
mice are similar to the
ß2m-/- mice with
virtually no TCRß+
CD8ß+ cells present in the intestine
(1.0 ± 0.7%) compared with control animals
(p = 0.00001). Moreover, the total cell number
of TCRß+ CD8ß+
IEL in Kb-/-Db-/- mice
is reduced 
15 times compared with the wild type (see Table I).
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ß+ CD8+ IEL are not
dependent upon MHC class Ia molecules
The percentage of TCRß+
CD8+ cells is greatly decreased in
ß2m-/- mice (1.8
± 0.6%) and moderately decreased in TAP-/-
(4.4 ± 2.5%) when compared with control animals (10.9 ±
4.0%) (Fig. 2). By contrast, in
Kb-/-Db-/- animals the
CD8+ population is present (Fig. 1), and
its percentage among total IEL (21 ± 7.7%) is increased when
compared with C57BL/6 mice (p = 0.0028) (Fig. 2). Furthermore, the total cell number of
TCRß+ CD8+ is
increased three times when compared with C56BL/6 mice and 35 times when
compared with ß2m-/- or
TAP-/- mice (see Table I). Hence, it appears
that at least some TCRß+
CD8+ IEL are not dependent upon the MHC
class Ia molecules K and D, and that the number of such cells may be
negatively regulated by classical class I expression.
The difference between
Kb-/-Db-/- and
ß2m-/- mice suggests
that the TCRß+
CD8+ population requires a class Ib
molecule(s). Because CD1 has been reported to be expressed in the
intestinal epithelium, we used CD1-/- mice to
test for a possible role for this class I molecule. The five
populations of TCRß+ IEL detected in control
animals were also present in CD1-deficient mice (Fig. 1), and the
percentages of the different TCRß+
populations among total IEL found in CD1-/-
were not significantly different from the ones found in control animals
(Fig. 2).
In agreement with our earlier results (8), we found that
the DP IEL are greatly decreased in
ß2m-/- mice, but they
are not decreased in either TAP 1-/- or
Kb-/-Db-/- mice (Fig. 2). While these data suggest a possible role for class I molecules
other than K or D either in the induction or maintenance of DP IEL,
this population tends to be quite variable, and it should be noted that
other studies have reported only a small decrease (6) or
even an increase in DP IEL in
ß2m-/- mice
(7).
Phenotypic analysis of TCRß+
CD8+ IEL in Kb-/-Db-/-
mice
The expression of the homodimeric form of the CD8 molecule has
been shown to define a highly unusual subset of T cells that fail to
express markers normally found on mature T cells, including CD28, CD5,
and CD90 (Thy1.2) (17, 19, 20). They have been described
to express the activation marker CD44 as well as CD103
(21), the subunit of a mucosal-specific integrin
(22). TCRß+
CD8+ from the
Kb-/-Db-/- mice are
CD5- CD28- and
CD90-, while they express CD103, CD44, CD16, and
low levels of CD122 (Fig. 3), suggesting
that the population of CD8+ IEL present in
the class Ia-deficient mice is similar to the population found in
normal mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ CD8+ IEL
population is present in
Kb-/-Db-/- mice, while
the TCRß+ CD8ß+
population is missing. The different requirements for K and D by some
TCRß+ CD8+ are
consistent with the results from earlier studies showing that the two
types of IEL also differ with regard to cell surface protein
expression, TCR repertoire, and perhaps thymus dependence (18, 20, 23). The TCRß+
CD8+ IEL in
Kb-/-Db-/- mice have a
cell surface phenotype similar to their counterparts in normal mice,
and their Vß repertoire as assessed by flow cytometry is also similar
(data not shown), suggesting that this population in the class
Ia-deficient animals is not aberrant.
Previously we reported that TAP 1-/- mice had
increased numbers of TCRß+
CD8+ and CD8ß+
when compared with
ß2m-/- mice
(8). We interpreted these data to suggest that some
TCRß+ CD8+ IEL are
positively selected by TAP-independent but
ß2m-dependent nonclassical class I molecules
expressed in the intestine. Both the TL Ag, encoded by the
T3/T18 genes, and the CD1 molecule, fit these
TAP-independent but ß2m-dependent criteria, and
both molecules have been reported to be highly expressed by intestinal
epithelial cells (2, 3, 4). Several subsequent studies,
however, have failed to find abundant CD1 expression by mouse
intestinal epithelial cells, and this issue regarding CD1 expression
remains controversial. Although a minority of
TCRß+ CD8+ IEL could
be selected by CD1, no significant differences could be observed
between the IEL of control and CD1-/- animals,
suggesting that the CD1 molecule is not required for the majority of
TCRß+ CD8+ IEL.
Consistent with this, the TCRß+ CD8+ IEL
found in the Kb-/-Db-/- mice do not resemble
typical NK T cells with regard to skewing of the Vß repertoire, the
presence of the predominant V14 rearrangement, and the NK1.1 marker
expression (data not shown). TL is expressed at high levels in the
epithelium of the small intestine, and it remains a candidate molecule
for the selection of some TCRß+ IEL. The
present results from
Kb-/-Db-/- mice
suggest, however, that the increased percentage of
TCRß+ CD8ß+ IEL
in TAP 1-/- mice compared with
ß2m-/- mice is due in
part to the slightly increased level of K and D expression in the
absence of TAP (13). Furthermore, comparison of the four
types of mice studied here further suggests that some
TCRß+ CD8+ IEL
require a nonclassical class I molecule, as well as a functional TAP
molecule. The nonclassical class I molecule in question could be one of
those that require TAP for normal levels of surface expression, such as
Qa-1 (24), or a TAP-dependent set of ligands loaded into a
molecule that otherwise does not require TAP for surface expression,
such as the TL Ag (9, 25).
Perhaps the simplest explanation for the results presented here is that
class Ia molecules are required for the positive selection and/or
expansion of the majority of TCRß+
CD8ß+ IEL, while class Ib molecule(s) that
require TAP function, either for surface expression or for the loading
of particular ligands, are required for the development of most of the
TCRß+ CD8+ IEL.
It is likely, however, that some TCRß+
CD8+ IEL are selected by K and D molecules.
The analyses of two TCR transgenic models on the RAG-deficient
background, the H-Y specific B6.2.16 TCR, and the influenza
peptide-specific F5 TCR, have indicated that expression of the proper K
and D alleles and selecting peptides are required for the presence of
TCR transgene+ CD8+
IEL (26, 27). Therefore, TCRß+
CD8+ IEL are likely to be a heterogeneous
population in terms of their requirement for classical vs nonclassical
class I molecules.
It also is possible that the expression of CD8 homodimers by IEL
is not entirely associated with a conventional positive selection
process driven by class I molecules. CD4+ T cells
from spleen or lymph node can acquire CD8 expression and become
DP when they have migrated to the epithelium of the intestine
(28). By analogy, the DN T cells may also acquire
CD8 expression in the intestine following activation or migration
to that site.
Finally, it is striking that the TCRß+
CD8+ IEL show a statistically significant
increase in percentage in
Kb-/-Db-/- mice when
compared with wild-type controls (Fig. 2). The increase in the
percentage of cells with this phenotype is over and above the increases
both in total IEL number and the number of IEL with other phenotypes
(Table I). Analysis of IEL from (C57BL/6 x
129)F1 mice did not reveal any increase either in
total IEL or the percentage of TCRß+
CD8+ IEL (data not shown). This
demonstrates that the increase observed is not due to the small
proportion of residual 129 genes in the
Kb-/-Db-/- mice that
have been back-crossed three times to C57BL/6. These data suggest that
IEL populations are under negative regulation by K and D molecules, as
well as positive regulation that can be conducted by other class I
molecules. There are two possible mechanisms for such negative
regulation. First, K and D molecules themselves, or peptides derived
from them, might modulate the expansion or differentiation of IEL by
binding to inhibitory NK receptors expressed by these lymphocytes.
Alternatively, it is possible that the TCRß+
CD8ß+ IEL, which are absent in
Kb-/-Db-/- mice, might
themselves negatively regulate other IEL populations by some unknown
mechanism.
In summary, the findings here emphasize the differences between
subpopulations of TCRß+
CD8+ IEL and
TCRß+ CD8ß+ IEL,
they show that some TCRß+
CD8+ IEL are K and D independent to a
surprising degree, and they demonstrate a likely negative regulation by
K and/or D molecules, highlighting the unique and complex relationship
between TCRß+ CD8+ IEL
and class I proteins.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint request to Dr. Mitchell Kronenberg, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address:
3 Abbreviations used in this paper: IEL, intraepithelial lymphocyte; ß2m, ß2-microglobulin; TL, thymus leukemia; DN, double negative; DP, double positive.
Received for publication June 25, 1999. Accepted for publication August 16, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells develop normally in ß2-microglobulin- deficient mice. Proc. Natl. Acad. Sci. USA 89:653.+ intestinal intraepithelial T cells in ß2-microglobulin- and/or TAP1-deficient mice. J. Immunol. 156:2710.[Abstract]
ß T cells by the class Ib gene product, Qa-1(b). J. Exp. Med. 188:961.Eß7 integrin. Nature 372:190.[Medline]
and CD8ß T lymphocytes. Proc. Natl. Acad. Sci. USA 96:5628. in vivo. J. Immunol. 154:2678.[Abstract]
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