Primary membrane T cell immunodeficiencies

CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY 61,

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Primary Membrane T Cell Immunodeficiencies 1 FRAN(~OISE LE DEIST, GENEVIEVE DE SAINT BASILE, FABIENNE MAZEROLLES, GABRIELA THOENES, JEAN-PIERRE DE VILLARTAY, NADINE CERF-BENSUSSAN, BARBARA LISOWSKA-GROSPIERRE, CLAUDE GRISCELLI, AND ALAIN FISCHER I N S E R M U 132, Hfpital Necker Enfants Malades, 149 rue de S~vres, 75743 Cedex 15, Paris, France

Primary membrane T cell immunodeficiencies (ID) have recently been characterized. In this paper we describe the main findings about the leukocyte adhesion deficiencies (LAD), the ID with low expression of the T cell receptor/CD3 complex, and the Omenn's syndrome. LAD is a consequence of mutations in the B-chain-encoding gene of the leukocyte adhesion proteins. Functional consequences mainly affect phagocytic ceils which are incapable of transendothelial migration. Effector T lymphocyte functions are, however, also impaired, i.e., helper T cell activity and cytotoxicity. The latter defect may account for the inability of LAD patients to reject HLA nonidenticalbone marrow. Low expression of the T cell receptor CD3 complex is a rare entity characterized by a profoundly diminished expression of the whole complex on all T cells. The basic defect has not yet been unravelled. Interestingly, such T cells differentiate normally and can be activated by some antigens while anti-CD3 and anti-CD2 antibodies are not efficient. In five patients with Omenn's syndrome (combined immunodeficiency with eosinophilla), oligoclonal T cells were detected in blood, skin, and gut. These T ceils are also in vivo activated. Since in one family, one sibling presented with typical SCID, i.e., alymphocytosis, and another with the Omenn's syndrome, it is proposed that the latter syndrome may correspond to a form of leakiness of SCID as found in the mice SCID model. 9 199z Academic Press, Inc.

In this paper we summarize recent findings on three primary immunodeficiencies characterized by membrane T cell defects, the leukocyte adhesion deficiency (LAD) (defective expression of LFA-1 on T cells), the immunodeficiency with low expression of the T cell receptor/CD3 complex, and the immunodeficiency with eosinophila (possible limited diversity of the T cell receptor).

LEUKOCYTE ADHESION DEFICIENCY

LAD is characterized by a defective expression of three related leukocyte adhesion molecules, i.e., LFA-1, Mac-l, and p150-95. These molecules are heterodimers that share a common 13 subunit (CD18) and have specific r subunits (CD1 la, b, c, respectively) (1). They represent a subgroup of the integrin family. The disease has an autosomal recessive inheritance, with the affected locus being mapped on chromosome 21 q 22.3 (2, 3). There are about 80 known cases that have been described throughout the world, i.e., Europe, Middle East, Japan, and America. Moderate and severe phenotypes have been characterized according to the Presented as part of the first Jeffrey Modell Symposium entitled "New Concepts in Immunode* ficiency Disease," April 18-19, 1990, Mount Sinai Medical Center, New York. $56 0090-1229/91 $1.50 Copyright 9 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

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level of expression of all three heterodimers on leukocytes (2, 4). A residual expression is found in the moderate phenotype. Affected patients suffer from repeated infections that usually do not lead to death before adulthood. In contrast, in the complete type, which is characterized by an undetectable expression of the adhesion molecules, life-threatening bacterial infections often cause death within the first years of life. It is worth noting that most of the infections are of bacterial origin and that the hallmark of these infections is the absence of pus, i.e., the consequence of a defective adhesion and migration of phagocytic cells (2). Evidence has been given that the primary defect affects the subunit-encoding gene. Indeed, biosynthetic studies have revealed that patients' leukocytes normally synthetize the tt subunit precursors while the 13subunit if often not synthesized (2, 5). In some patients, the 13 subunit can be detected, but there is no et-13 subunit association. Similarly, the 13 subunit-specific mRNA is or is not present (6-8). Hibbs et al. (9) have demonstrated that a 13 subunit-encoding gene anomaly is causal since transfection of normal 13 subunit-encoding cDNA into patient's B cells resulted in a rescue of LFA-1 expression. At least five classes of mutations exist according to the detectable level of 13 chain mRNA, the presence of a 13 subunit precursor, and the level of membrane a13 complex expression (4, 7, I0). In a small number of patients, mutations have been characterized as either a single point mutation or as the creation of an alternative splice site leading to the deletion of 90 nucleotide exon (1 I). Although the in vivo immune deficiency does not evoke a functional T cell deficiency, in vitro and in vivo T cell dysfunctions have been observed. T cell activation by antigens or allogeneic cells, as well as delayed-type hypersensitivity, can be initiated, whereas anti-CD3-mediated T cell activation has been found impaired (12). Cytotoxic T and non T cell functions are defective (4, 13). This does not lead to an increased susceptibility to viral infections. The disease may, however, be associated with an absence of rejection H L A nonidentical marrow which has been efficiently used as a therapy of LAD (14). In some patients, it was found that antibody responses after immunizations were absent; chronic infections were, however, able to induce an antibody response (15). In vitro LFA-I(-) T cells were found to poorly help H L A identical B cells from a healthy sibling for antibody responses to influenza virus (16). It is very likely that the partial deficiency o f T cell effector functions (cytotoxicity and help) rely on defective adhesion--as found for T to B cell binding (2, 4). Moreover, Dustin and Springer (17) have shown that a transient upregulation of T cell adhesion that is triggered by T cell activation relies on an alteration of LFA-1 affinity. Such upregulation does not occur for LFA-I(-) T cells. However, LFA1(-) T cells can be induced to bind normally to B cells by hyperactivation with ionomycin, phorbol esters, and IL2 (16). Together with the CD2-LFA-3 adhesion pathway and possibly others (involving VLA molecules), these findings may account for the moderate consequences on T cell functions of the absence of LFA-1. The absence of expression of LFA-1 may also diminish the migration pattern of lymphocytes since lymphoid organs from patients with LAD were found hypoplasic postmortem (18).

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LE DEIST ET AL. IMMUNODEFICIENCY WITH LOW EXPRESSION OF THE T CELL RECEPTOR (TCR)/CD3 COMPLEX

The TCR/CD3 complex is composed of the edl3 or ~/~ subunits of TCR associated with the CD3 ~/, ~, 9 subunits, the CD3 ~ homodimer, or CD3 ~/~ heterodimers (19). CD3 subunits are supposedly involved in signal transduction. Regueiro et al. (20) have described a low expression of the TCR/CD3 complex in two siblings with a mild immunodeficiency. They have found a defective biosynthesis of the CD3 ~ chain and proposed that patients T cells express an immature form of the CD3frCR complex not associated with CD3 ~ and are poorly glycosylated (20). We have recently observed a third patient who is a 3-year-old boy with mild bacterial lung infections. The TCR/CD3 complex was found poorly expressed on all types of T lymphocytes (TCR etl3 or ",//~) with whatever T cells were in a resting or activated state. There was a residual expression of the TCR/ CD3 complex that did not exceed 10% of normal. Biosynthetic studies have shown a quantitatively normal synthesis of CD3 ~ (21) which suggests that the primary defect relies on a general regulatory anomaly or on a defective synthesis of one other subunit, thereby limiting the number of complexes formed. Studies of the CD3 subunits mRNA expression are presently ongoing. Immunological consequences of the defect are worth analyzing. T cell differentiation appeared normal since there is no gross anomaly either in T cell numbers or in membrane molecules expression excluding TCR/CD3. Self to nonself discrimination is normal since patients T cells are fully activated by allogeneic cells but not by their own cells. However, antibodies to CD3 and also to CD2 were unable to trigger T cell activation as measured by both calcium flux and cell proliferation. This confirms that the CD3 complex is required for the transduction of CD2-mediated activation (22, 23). Surprisingly, it was found that antigens such as candida antigens and tetanus toxoid could induce patients T cell proliferation following infection and immunization, respectively. Antigen-activated T cell blasts still poorly expressed the TCR/CD3 complex. This observation indicates that the ag/MHC complex may be a more efficient ligand of the TCR/CD3 complex than anti-CD3 antibodies for triggering T cell activation. It is also not know how T cell differentiation does occur in the thymus in the context of a partial CD3/TCR expression defect. IMMUNODEFICIENCY WITH EOSINOPHILIA (OMENN'S SYNDROME) In 1965, Omenn reported on a syndrome observed in several infants in a large pedigree, which was characterized by a diffuse erythrodermia associated with alopecia, protracted diarrhea, failure to thrive, and life-threatening infections (24). Other patients have been found since and a profound T and B cell immunodeficiency was observed in these patients (25-27). Skin and gut biopsies revealed infiltration by T lymphocytes with a graft versus host-like reaction aspect. Finally, the syndrome has been found to be curable by allogeneic bone marrow transplantation. We have further characterized T lymphocytes in five patients that we have recently studied. The number of blood T lymphocytes increased from 10,000 to 20,000/g.l. These T cells were not of maternal origin, thus ruling out the hypothesis

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o f a materno-fetal GVHD. Blood T cells were found to express activation antigens such as the p55 subunit of the IL2 receptor or H L A class II molecules. They are activatable to some extent by lectins and antibodies to CD3 and CD2 while no antigen-induced activation could be induced. Interestingly, it was found that there was a predominant T cell subset in each patient, i.e., TCR af3 + C D 4 + , TCR cxl3 + CD8 + , TCR a13 + C D 4 - C D 8 - as found in a recently published case (28) or TCR ~/8 + . Similar findings were made on skin and gut biopsies in two patients. By studying the rearrangement of the T cell receptor of the blood T cells using cxl3, ~/, and ~8 probes, it was found that discrete bands could be detected in four patients (one to four bands) which suggests, together with the previous findings, the existence of only a limited number of T cell clones in some of these patients. They may correspond to a leakiness in a context of SCID as observed in nude and SCID mice (29, 30). This hypothesis is further suggested by the observation in a same family of one patient with a classical type of SCID, i.e., with alymphocytosis, and of a sibling with the Omenn's syndrome. In this setting, one may envisage that the limited number of T cell clones that dramatically expand exert autoimmune responses directed at skin and gut epithelia. REFERENCES 1. Springer, T. A., Dustin, M. L., Kishimoto, T. K., and Marlin, S. D., The lymphocyte functionassociated LFA-I, CD2 and LFA-3 molecules: Cell adhesion receptors of the immune system. Annu. Rev. Immunol. 5, 223, 1987. 2. Anderson, D. C., and Springer, T. A., Leukocyte adhesion deficiency: An inherited defect in the Mac-l, LFA-I and p150-95 glycoproteins. Annu. Rev. Med. 38, 176, 1987. 3. Corbi, A. L., Larson, R. S., Kishimoto, T. K., et al., Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-I, Mac-I and p150-95: Identification of a gene cluster involved in cell adhesion. J. Exp. Med. 67, 1597, 1988. 4. Fischer, A., Lisowska-Grospierre, B., Anderson, C. D., and Springer, T. A., Leukocyte adhesion deficiency: Molecular basis and functional consequences. Immunodef. Rev. 1, 39, 1988. 5. Dimanche, M. T., Le Deist, F., Fischer, A., et al., LFA-I 13chain synthesis and degradation in patients with LAD. Eur. J. Immunol. 17, 417, 1987. 6. Dana, N., Clayton, L. K., Tenen, D. G., et al., Leukocytes from four patients with complete or partial leu-Cam deficiency contain the common beta subunit precursor and beta subunit messenger RNA. J. Clin. Invest. 79, 1010, 1987. 7. Kishimoto, T. K., Hollander, N., Roberts, T. M., Anderson, D. C., and Springer, T. A., Heterogeneous mutations in the 13 subunit common to the LFA-I, Mac-1 and p150-95 glycoproteins cause LAD. Cell 50, 193, 1987. 8. Dimanche-Boitrel, M. T., Guyot, A., De Saint Basile, G., et al., Heterogeneity in the molecular defect leading to the LAD. Fur. J. Immunol. 18, 1575, 1988. 9. Hibbs, M. L., Wardlaw, A. J., Stacker, S. A., et al., Transfection of cells from patients with leukocyte adhesion deficiency with an integrin 13subunit (CDI8) restores LFA-I expression and function. J. Clin. Invest. 85, 674, 1990. 10. Arnaout, M. A., Dana, N., Gupta, S. K. el al., Point mutations impairing cell surface expression of the common 13subunit (CDI8) in a patient with leukocyte adhesion molecule deficiency. J. Clin. Invest. 85, 977, 1990. 11. Kishimoto, T. K., O'Connor, K., and Springer, T. A., Leukocyte adhesion deficiency: Aberrant splicing of a conserved integrin sequence causes a moderate deficiency phonotype. Biol. Chem. 264, 3588, 1989. 12. Van Noesel, C., Miedema, F., Brouwer, M., et al., Regulatory properties of LFA-I c~and 13chains in human T-lymphocyte activation. Nature 333, 850, 1988.

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13. Mentzer, S. J., Bierer, B. E., Anderson, D. C., Springer, T. A., and Burakoff, S. J., Abnormal cytolytic activity of LFA-I deficient human cytolytic T lymphocyte clones. J. Clin. Invest. 78, 1387, 1986. 14. Le Deist, F., Blanche, S., Keable, H., et al., Sucessful HLA non identical bone marrow transplantation in three patients with LAD. Blood 74, 512, 1989. 15. Fischer, A., Durandy, A., Sterkers, G., and Griscelli, C., Role of LFA-I in antigen-specific helper T lymphocyte-B lymphocyte interaction. J. Immunol. 136, 3198, 1986. 16. Mazerolles, F., Lumbroso, C., Lecomte, O., Le Deist, F., and Fischer, A., The role of LFA-I in the adherence of T lymphocytes to B lymphocytes. Eur. J. Immunol. 18, 1229, 1988. 17. Dustin, M. L., and Springer, T. A., T cell receptor cross-linking transiently stimulates adhesiveness through LFA-I. Nature 431, 619, 1989. 18. Nunoi, H., Yanabe, Y., Higushi, S., et al., Severe hypoplasia of lymphoid tissues in Mol deficiency. Hum. Pathol. 19, 753, 1988. 19. Clevers, H., Alarcon, B., Wileman, T., and Terhorst, C., The T-cell receptor/CD3 complex: A dynamic protein ensemble. Annu. Rev. Immunol. 6, 629, 1988. 20. Alarcon, B., Regueiro, J. R., Arnaiz-Villena, A., and Terhorst, C., Familial defect in the surface expression of the T-cell receptor-CD3 complex. N. Engl. J. Med. 319, 1203, 1988. 21. Thoenes, G., Le Deist, F., Fischer, A., et al., Defect in expression of TCR/CD3 complex not due to lack of the CD3 zeta chain. N. Engl. J. Med. 322, 1399, 1990. 22. Breitmeyer, J., Daley, J., Levine, N., and Schlossman, S. F., The TII (CD2) molecule is functionaUy linked to the T3/Ti T cell receptor in the majority of T cells. J. lmmunol. 139, 2899. 23. Brown, M. H., Cantrell, D. A., Brattsand, G., Crumpton, M. J., and Gullberg, M. The CD2 antigen associates with the T cell antigen receptor/CD3 antigen complex on the surface of human T lymphocytes. Nature 339, 551. 24. Omenn, G. S., Familial reticuloendotheliosis with eosinophilia. N. Engl. J. Med. 273, 427, 1%5. 25. Barth, R. F., Vergara, G. G., Khurana, S. K., et al., Rapidly fatal familial histiocytosis associated with eosinophilia and primary immunological deficiency. Lancet 2, 503, 1972. 26. Cederbaum, S. D., Niwayama, G., Stiehm, E. R., et al., Combined immunodeficiency and retieuloendotheliosis with eosinophilia. J. Pediatr. 85, 466, 1974. 27. Le Deist, F., Fischer, A., Durandy, A., et al., D6ficit immunitaire mixte et grave avec hyper6osinophilie: Etude immunologique de cinq observations. Arch. Ft. Pediatr. 42, 11, 1985. 28. Wirt, D. P., Brooks, E. G., Vaidya, S., et al., Novel T-lymphocyte population in combined immunodeficiencywith features of graft versus host disease. N. Engl. J. Med. 321,370, 1989. 29. MacDonald, H. R., Lees, R. K., Bron, C., et al., T cell antigen receptor expression in athymic (nu/nu) mice: Evidence for an oligoclonal chain repertoire. J. Exp. Med. 166, 195, 1987. 30. Bosma, G. C., Fried, M., Custer, R. P., et al., Evidence of functional lymphocytes in some leaky scid mice. J. Exp. Med. 167, 1016, 1988. Received June 10, 1991; accepted June 14, 1991