The major histocompatibility complex (MHC) class I molecules are ubiquitous cell surface molecules involved in the cell-mediated immune response. We show here, using a number of different, independent approaches, that these proteins are an essential component of the host cell surface receptor involved in Theileria parva sporozoite invasion. Monoclonal antibodies (mAbs) reactive with common determinants on MHC class I molecules and with beta-2 microglobulin inhibited sporozoite entry by specifically preventing the initial binding event. However, in experiments using lymphocytes from heterozygous cattle in which at least four MHC class I gene products are expressed, mAbs which reacted with only one of these products did not inhibit entry. Using a series of bovine deletion mutant cell lines from which one or both MHC class I haplotypes had been lost, sporozoite binding and entry clearly correlated with the level of class I surface expression. While the level of sporozoite entry into cells in which one of the MHC class I haplotypes was lost was only slightly lower than into the parent cells, in a double deletion cell line having less than 5% of the class I expression of the parent cells the level of infection was only 4.3% of that into the parent cells. Furthermore, sporozoite entry into cells from a spontaneously arising mutant cell line exhibiting low levels of class I expression was correspondingly low. Treatment of lymphocytes with IL-2 produced a significant increase in host cell susceptibility and sporozoite entry and this increase correlated with either an increase in the number of target molecules per host cell, or in the binding of bovine MHC class I molecules to the mAbs. In particular, a significant increase in the level of reactivity with mAb W6/32 was observed. Lastly, we show that parasite entry can be competitively inhibited with an isolated sporozoite surface protein, p67. However, p67 binds weakly to lymphocyte surface molecules and initial attempts to use p67 to isolate the relevant host cell molecule(s) have not been successful.

REFERENCES

Alexander
J.
,
Russell
D. G.
(
1992
).
The interaction of Leishmania species with macrophages.
Advan. Parasitol
31
,
175
254
Baldwin
C. L.
,
Black
S. J.
,
Brown
W. C.
,
Conrad
P. A.
,
Goddeeris
B. M.
,
Kinuthia
S. W.
,
Lalor
P. A.
,
MacHugh
N. D.
,
Morrison
W. I.
,
Morzaria
S. P.
,
Naessens
J.
,
Newson
J.
(
1988
).
Bovine T cells, B cells, and Null cells are transformed by the protozoan parasite Theileria parva.
Infect. Immunity
56
,
462
467
Bensaid
A.
,
Naessens
J.
,
Kemp
S. J.
,
Black
S. J.
,
Shapiro
S. Z.
,
Teale
A. J.
(
1988
).
An immunochemical analysis of class I (BoLa) molecules on the surface of bovine cells.
Immunogenetics
27
,
139
144
Bensaid
A.
,
Kaushal
A.
,
MacHugh
N. D.
,
Shapiro
S. Z.
,
Teale
A. J.
(
1989
).
Biochemical characterization of activation-associated bovine class I major histocompatibility complex antigens.
Animal Genet
20
,
241
255
Bensaid
A.
,
Kaushal
A.
,
Baldwin
C. W.
,
Clevers
H.
,
Young
J. R.
,
Kemp
S. J.
,
MacHugh
N. D.
,
Toye
P. G.
,
Teale
A. J.
(
1991
).
Identificationof expressed bovine class I MHC genes at two loci and demonstration of physical linkage.
Immunogenetics
33
,
247
254
Bjorkman
P. J.
,
Saper
M. A.
,
Samraoui
B.
,
Bennett
W. S.
,
Strominger
J. L.
,
Wiley
D. C.
(
1987
).
The foreign antigen site and T cell recognition regions of class I histocompatibility antigens.
Nature
329
,
512
518
Bourguignon
L. Y. W.
,
Bourguignon
G. J.
(
1984
).
Capping and the cytoskeleton.
Int. Rev. Cytol
87
,
195
224
Breau
W. C.
,
Atwood
W. J.
,
Norkin
L. C.
(
1992
).
Class I major histocompatibility proteins are an essential component of the simian virus 40 receptor.
J. Virol
66
,
2037
2045
Browne
H.
,
Smith
G.
,
Beck
S.
,
Minson
T.
(
1990
).
A complex between the MHC class I homologue encoded by human cytomegalovirus and beta-2 microglobulin.
Nature
347
,
770
772
Burgert
H.-G.
,
Kvist
S.
(
1985
).
An adenovirus Type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens.
Cell
41
,
987
997
Capps
G. G.
,
Van Kampen
M.
,
Ward
C. L.
,
Zuniga
M. C.
(
1989
).
Endocytosis of the class I major histocompatibility antigen via a phorbol myristate acetate-inducible pathway is a cell-specific phenomenon and requires the cytoplasmic domain.
J. Cell Biol
108
,
1317
1329
Chatterjee
D.
,
Maizel
J. V.
(
1984
).
Homology of adenoviral E2 glycoprotein with HLA-DR heavy chain.
Proc. Nat. Acad. Sci. USA
81
,
6039
6043
Dasgupta
J. D.
,
Yunis
E. J.
(
1987
).
Receptor-like role of HLA-class I antigens: regulation of T cell activation.
J. Immunol
139
,
672
677
Diamond
M. S.
,
Springer
T. A.
(
1994
).
The dynamic regulation of integrin adhesiveness.
Curr. Biol
4
,
506
517
Dobbeleare
D. A. E.
,
Spooner
P. R.
,
Barry
W. C.
,
Irvin
A. D.
(
1984
).
Monoclonal antibody neutralises the sporozoite stage of different Theileria parva stocks.
Parasite Immunol
6
,
361
370
Dobbeleare
D. A. E.
,
Shapiro
S. Z.
,
Webster
P.
(
1985
).
Identification of a surface antigen on Theileria parva sporozoites by monoclonal antibody.
Proc. Nat. Acad. Sci. USA
82
,
1771
1775
Falkow
S.
,
Isberg
R. R.
,
Portnoy
D. A.
(
1992
).
The inter-action of bacteria with mammalian cells.
Annu. Rev. Cell Biol
8
,
333
363
Faull
R. J.
,
Kovach
N. L.
,
Harlan
J. M.
,
Ginsberg
M. H.
(
1993
).
Affinity modulation of integrin5 1: Regulation of the functional response by soluble fibronectin.
J. Cell Biol
121
,
155
162
Fawcett
D. W.
,
Doxsey
S.
,
Stagg
D. A.
,
Young
A. S.
(
1982
).
The entry of sporozoites of Theileria parva into bovine lymphocytes in vitro. Electron microscopic observations. Eur.
J. Cell Biol
27
,
10
21
Garcia-del Portillo
F.
,
Pucciarelli
M. G.
,
Jefferies
W. A.
,
Finlay
B. B.
(
1994
).
Salmonella typhimurium induces selective aggregation and internalization of host cell surface proteins during invasion of epithelial cells.
J. Cell Sci
107
,
2005
2020
Hasty
D. L.
,
Oftek
I.
,
Courtney
H. S.
,
Doyle
R. J.
(
1992
).
Multiple adhesins of streptococci.
Infect. Immunity
60
,
2147
2152
Lalor
P. A.
,
Morrison
W. I.
,
Goddeeris
B. M.
,
Jack
R. J.
,
Black
S. J.
(
1986
).
Monoclonal antibodies identify phenotypically and functionally distinct cell types in the bovine lymphoid system.
Vet. Immunol. Immunopathol
13
,
121
140
Lentz
T. L.
(
1990
).
The recognition event between virus and host cell receptor: a target for antiviral agents.
J. Gen. Virol
71
,
751
766
Lollo
B. A.
,
Chan
K. W. H.
,
Hanson
E. M.
,
Moy
V. T.
,
Brian
A. A.
(
1993
).
Direct evidence for two affinity states for lymphocyte function-associated antigen 1 on activated T cells.
J. Biol. Chem
268
,
21693
21700
Morrison
W. I.
,
Goddeeris
B. M.
,
Brown
W. C.
,
Baldwin
C. L.
,
Teale
A. J.
(
1989
).
Theileria parva in cattle: characterization of infected lymphocytes and the immune response they provoke.
Vet. Immunol. Immunopathol
20
,
213
237
Musoke
A. J.
,
Nantulya
V. M.
,
Buscher
B.
,
Masake
R. A.
,
Otim
B.
(
1982
).
Bovine immune response to Theileria parva: neutralizing antibodies to sporozoites.
Immunology
45
,
663
668
Musoke
A. J.
,
Nantulya
V. M.
,
Rurangirwa
F. R.
,
Buscher
G.
(
1984
).
Evidence for a common protective antigenic determinant on sporozoites of several Theileria parva strains.
Immunology
52
,
231
238
Musoke
A.
,
Morzaria
S.
,
Nkonge
C.
,
Jones
E.
,
Nene
V.
(
1992
).
A recombinant sporozoite surface antigen of Theileria parva induces protection in cattle.
Proc. Nat. Acad. Sci. USA
89
,
514
518
Naessens
J.
,
Newson
J.
,
Bensaid
A.
,
Teale
A. J.
,
Magondu
J. G. S. J.
,
Black
S. J.
(
1985
).
De novo expression of T cell markers on Theileria parva -transformed lymphoblasts in cattle.
J. Immunol
135
,
4183
4188
Naessens
J.
,
Howard
C. J.
(
1991
).
Monoclonal antibodies reacting with bovine B cells (BoWC3, BoWC4 and BoWC5).
Vet. Immunol. Immunopathol
27
,
77
85
Nagai
Y.
(
1993
).
Protease-dependent virus tropism and pathogenicity.
Trends Microbiol
1
,
81
87
O'Reilly
K. L.
,
Eskra
L.
,
Spitter
G. A.
(
1991
).
Antibodies to non-clustered bovine antigens.
Vet. Immunol. Immunopathol
27
,
91
93
Park
L. S.
,
Friend
D.
,
Gillis
S.
,
Urdal
D. L.
(
1986
).
Characterization of the surface receptor for a multi-linkage colony-stimulating factor (CSF-2a).
J. Biol. Chem
261
,
205
210
Potter
T. A.
,
Rajan
T. V.
,
Dick
R. F.
,
Bluestone
J. A.
(
1989
).
Substitution at residues 227 of H-2 class I molecules abrogates recognition by CD8-dependent, but not CD8-independent cytotoxic T lymphocytes.
Nature
337
,
73
75
Schreiber
A. B.
,
Schlessinger
J.
,
Edidin
M.
(
1984
).
Interaction between major histocompatibility complex antigens and epidermal growth factor receptors on human cells.
J. Cell Biol
98
,
725
731
Sharon
M.
,
Gnarra
J. R.
,
Baniyash
M.
,
Leonard
W. J.
(
1988
).
Possible association between IL-2 receptors and class I HLA molecules on T cells.
J. Immunol
141
,
3512
3515
Shaw
M. K.
,
Tilney
L. G.
,
Musoke
A. J.
(
1991
).
The entry of Theileria parva sporozoites into bovine lymphocytes: evidence for MHC class I involvement.
J. Cell Biol
113
,
87
101
Shaw
M. K.
,
Tilney
L. G.
,
McKeever
D. J.
(
1993
).
Tick salivary gland extract and interleukin-2 stimulation enhance susceptibility of lymphocytes to infection by Theileriaparva sporozoites.
Infect. Immunity
61
,
1486
1495
Shivdasani
R. A.
,
Thomas
D. W.
(
1988
).
Molecular associations of IA antigens after T-B cell interaction. I. Identification of new molecular associations.
J. Immunol
141
,
1252
1260
Slater
R. D.
,
Benjamin
R. J.
,
Wesley
P. K.
,
Buxton
S. E.
,
Garrett
T. P. C.
,
Clayberger
C.
,
Krensky
A. M.
,
Norment
A. M.
,
Littman
D. R.
,
Parham
P.
(
1990
).
A binding site for the T cell co-receptor CD8 on the a3 domain of HLA-A2.
Nature
345
,
41
49
Toye
P. G.
,
MacHugh
N. D.
,
Bensaid
A. M.
,
Alberti
S.
,
Teale
A. J.
,
Morrison
W. I.
(
1990
).
Transfection into mouse L cells of genes encoding two serologically and functionally distinct bovine class I MHC molecules from a MHC-homozygous animal: evidence for a second class I locus in cattle.
Immunology
70
,
20
26
Williams
C. L.
,
Hayes
V. Y.
,
Hummel
A. M.
,
Tarara
J. E.
,
Halsey
T. J.
(
1993
).
Regulation of E-cadherin-mediated adhesion by muscarinic acetylcholine receptors in small cell lung carcinoma.
J. Cell Biol
121
,
643
654
Williams
D. J. L.
,
Newson
J.
,
Naessens
J.
(
1990
).
Quantitation of bovine immunoglobulin isotypes and allotypes using monoclonal antibodies.
Vet. Immunol. Immunopathol
24
,
267
283
Wise
K. S.
(
1993
).
Adaptive surface variation in mycoplasmas.
Trends Microbiol
1
,
59
62
Wood
C. L.
,
O'Durisio
M. S.
(
1985
).
Covalent cross-linking of vasoactive intestinal polypeptide to its receptors on intact human lymphoblasts.
J. Biol. Chem
260
,
1243
1247
This content is only available via PDF.