Original Article
Brief Report
Inherited and Somatic CD3ζ Mutations in a Patient with T-Cell Deficiency
N Engl J Med 2006; 354:1913-1921May 4, 2006
- Abstract
A four-month-old boy with primary immunodeficiency was found to have a homozygous germ-line mutation of the gene encoding the CD3ζ subunit of the T-cell receptor–CD3 complex. CD3ζ is necessary for the development and function of T cells. Some of the patient's T cells had low levels of the T-cell receptor–CD3 complex and carried the Q70X mutation in both alleles of CD3ζ, whereas other T cells had normal levels of the complex and bore the Q70X mutation on only one allele of CD3ζ, plus one of three heterozygous somatic mutations of CD3ζ on the other allele, allowing expression of poorly functional T-cell receptor–CD3 complexes.
Media in This Article
Figure 1
T-Cell Receptor–CD3 Expression by the Patient's T Cells.Figure 2
Detection of CD3ε and CD3ζ Proteins in the Patient's T Cells with Either High or Low Levels of the T-Cell Receptor–CD3 Complex.Article Activity
- Article
The antigen-receptor complex on the surface of T cells consists of a clonotypic heterodimer (α and β chains in most T cells) and four invariant signaling subunits: CD3γ, CD3δ, CD3ε, and CD3ζ. In mature T cells, the ζ chain synthesis regulates the assembly of complete T-cell–receptor complexes and their expression on the cell surface in the steady state.1 Complexes lacking the ζ chain are assembled in the Golgi apparatus, but instead of moving on to the plasma membrane, as normal complexes do, they are rapidly shunted to lysosomes for degradation.2 The CD3ζ chain contains three copies of the immunoreceptor tyrosine-based activation motif (ITAM).3 These activation motifs become phosphorylated on stimulation of the T-cell receptor by a ligand and then associate with the 70-kD zeta-associated protein (ZAP-70), a protein tyrosine kinase with a critical role in the initiation of T-cell signaling.4 Hence, in addition to controlling the expression of T-cell receptor–CD3 complexes on the plasma membrane, CD3ζ contributes to the mechanism of T-cell activation. Moreover, CD3ζ also participates in intrathymic T-cell differentiation, which is arrested in mice lacking CD3ζ.5-8
Severe combined immunodeficiency is a heterogeneous group of diseases characterized by a profound block in T-cell development or function.9 The absence of T cells causes defects in both cellular and humoral immunity. In patients lacking only mature T cells, mutations of the gene encoding the interleukin-7–receptor α chain10 and mutations of the CD45 gene have also been reported.11,12 A deficiency of B cells, natural killer cells, or both occurs in some cases of immunodeficiency. Cases of severe combined immunodeficiency with mutations in the CD3δ or CD3ε genes13,14 demonstrate the essential role of CD3δ and CD3ε in T-cell differentiation. We describe a child with severe immunodeficiency associated with CD3ζ deficiency.
Case Report
The patient, a boy of Caribbean origin, was of unknown paternity. Two older siblings were healthy. He presented at the age of four months with erythroderma, protracted diarrhea, and pulmonary abscesses caused by Pseudomonas aeruginosa. During the next two years, he had recurrent episodes of herpes simplex virus infection of the mouth and skin, two episodes of oral and skin infections with Candida albicans, and two pulmonary infections, one of which was caused by Streptococcus pneumoniae. The patient's T-cell counts were very low, B-cell counts were normal, and there was eosinophilia (1000 cells per cubic millimeter) (Table 1Table 1
A Comparison of Immunologic Function in the Patient and in Controls.). Neutrophil and platelet counts were normal. Lymphocytes of maternal origin could not be detected in the blood by fluorescence in situ hybridization, a finding that ruled out mother–infant graft-versus-host disease. Serum immunoglobulin levels were elevated (Table 1). IgM heterogeneity was restricted, and IgG autoantibodies against erythrocytes and neutrophils were detected. No antibodies were detected after immunization with tetanus toxoid, diphtheria toxoid, and poliovirus (Table 1). The patient received intravenous immune globulin therapy, antibiotics, and antifungal treatment. A haploidentical bone marrow transplantation, with the mother as the donor, was performed when the patient was 30 months old. The transplant resulted in sustained donor–recipient chimerism and correction of the immunodeficiency. Three years later, the patient is well and living at home. The study was approved by the institutional review board, and the patient's mother gave written informed consent for all investigations.Methods
Analysis of Immune Function
Immunofluorescence analysis, assays for proliferation of peripheral-blood mononuclear cells, and studies of natural-killer-cell cytotoxicity were performed as previously described.15-18 The Foxp3-specific monoclonal antibody (PCH101) was used according to the manufacturer's instructions. The serum immunoglobulin levels and the level of antibodies after immunization were determined by nephelometry and enzyme-linked immunosorbent assay for diphtheria and tetanus toxoids and polioviruses.
Immunoprecipitation and Western blot Analysis
Cell lysis, cell biotinylation, and immunoprecipitation of proteins were performed as described.19 Immunoprecipitates or lysates were subjected to sodium dodecyl sulfate–polyacrylamide-gel electrophoresis and blotted on polyvinylidene difluoride membranes (Millipore). Primary monoclonal antibodies specific for CD3ζ (6B10.2, Santa Cruz), CD3ε (UCHT1 and Apa1.1, provided by Dr. B. Alarcon of the University of Madrid), ZAP-70 (SC157, Santa Cruz; and clone 29, Transduction Laboratory), FcεRIγ (a gift from Dr. C. Bonnerot20), antiphosphotyrosine (4G10, UBI), and tubulin (Ab-1, Oncogene) were used. Specific proteins were detected with appropriate horseradish peroxidase–conjugated second antibodies (Jackson ImmunoResearch Laboratories) and the ECL detection system (Amersham Pharmacia Biotech).
Mutations
Genomic DNA and RNA were extracted from peripheral-blood mononuclear cells, T cells (with either high or low levels of the T-cell receptor–CD3 complex) sorted by a fluorescence-activated cell sorter (FACS), B-cell lines transformed with Epstein–Barr virus (EBV), and fibroblasts, as previously described.21 CD3ζ-specific reverse-transcriptase polymerase chain reaction was performed according to a standard method and specific primers (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). Polymerase-chain-reaction products either were sequenced directly, as previously described, or were cloned into Topo vectors (Invitrogen) and sequenced.
Results
Immunologic Investigations
The patient's T-cell counts were low at the age of 10 months and gradually increased until the age of 2 years, but the levels remained below normal values (Table 1). The levels of natural killer cells and B-cell counts were normal (Table 1). Ninety percent of circulating T cells expressed low levels of CD3ε and α/β T-cell receptors and were designated as the subgroup with low levels of the T-cell receptor–CD3 complex; the remaining 10 percent of T cells had normal levels of the T-cell receptor–CD3 complex (Figure 1AFigure 1
T-Cell Receptor–CD3 Expression by the Patient's T Cells.). We detected both CD4+ and CD8+ cells in the population that had low levels of the T-cell receptor–CD3 complex (Figure 1A and Table 1). In contrast, almost all the T cells with normal levels of the T-cell receptor–CD3 complex were CD4+ (Figure 1A and Table 1). Analysis by FACS of peripheral-blood mononuclear cells that were rendered permeable to allow entrance of analytical antibodies showed that the ζ chain was present mainly in cells that strongly expressed CD3ε (Figure 1E). Most of the T cells, including all the lymphocytes with normal levels of the T-cell receptor–CD3 complex, displayed a phenotype of memory T cells (CD45RO+CD27+CD28+CD31−) (Table 1). No CD3+CD4+Foxp3+ regulatory T cells could be detected (data not shown).In vitro, T-cell proliferation induced by phytohemagglutinin or CD3 antibodies was impaired, as compared with cells from control subjects, but the addition of interleukin-2 partially restored the response to CD3 antibodies (Table 1). The patient's T cells responded poorly to tetanus toxoid, as compared with T cells from an age-matched control subject. In contrast, sustained proliferation of T cells was observed on stimulation with phorbol myristate acetate and ionomycin (Table 1). Since the two pharmacologic agents act synergistically to enhance T-cell activation independent of T-cell receptors, these results indicate that the proliferative defect in the patient's T cells was restricted to the initial steps of T-cell receptor–CD3 signaling. Normal cytotoxic activity of natural killer cells was observed with the K562 cell line (Table 1).
Analysis of the T-Cell Receptor–CD3 Complex
With the use of appropriate antibodies, CD3ε and CD3ζ chains could not be precipitated from the plasma membranes of the patient's cells with low levels of the T-cell receptor–CD3 complex (Figure 2AFigure 2
Detection of CD3ε and CD3ζ Proteins in the Patient's T Cells with Either High or Low Levels of the T-Cell Receptor–CD3 Complex.). In whole-cell lysates, the CD3ε chain was detected, but the CD3ζ chain was undetectable. In contrast, the CD3ζ chain was detected by a Western blot analysis of plasma-membrane preparations of the patient's cells with normal levels of the T-cell receptor–CD3 complex but in somewhat lower amounts than in control cells (Figure 2B). Since the FcεRIγ chain, which is involved in signaling the antigen receptor of B cells, is also found in T-cell receptor–CD3 complexes of intraepithelial T cells in mice,22 we looked for this chain in the patient's T cells with normal levels of the T-cell receptor–CD3 complex. It was not found in plasma-membrane preparations obtained from the patient's T cells with normal levels of the T-cell receptor–CD3 complex but was present in normal amounts in the whole-cell lysate of these cells (Figure 2B). ZAP-70 was present in normal amounts in the patient's CD3-activated T cells with normal levels of the T-cell receptor–CD3 complex but was not phosphorylated (Figure 2C).Analysis of the CD3ζ Gene
Given the defective expression of CD3ζ by the patient's T cells with low levels of the T-cell receptor–CD3 complex, we sequenced the CD3ζ gene in DNA from lines of his EBV-transformed B cells and fibroblasts and from his mother's T cells. A homozygous C-to-T transition at nucleotide 207 of the coding sequence, leading to a nonsense mutation at position 70 (Q70X), was detected (Figure 3AFigure 3
CD3ζ Gene Mutations.). This change was not found in 200 chromosomes from control subjects of the same ethnic origin as the patient and his mother. The premature stop codon of Q70X is located within the first ITAM domain, immediately upstream from the first YXXL motif, precluding expression of all ITAM motifs and thus any interaction with the tyrosine kinase ZAP-70. A heterozygous Q70X mutation was identified in the mother's DNA, but no material was available from the father. Expression of the T-cell receptor–CD3 complex by the mother's T cells was normal (not shown), a finding consistent with inheritance of an autosomal recessive mutation of the CD3ζ gene.We detected the homozygous Q70X mutation in DNA from the patient's cells with low levels of the T-cell receptor–CD3 complex and in complementary DNA produced from messenger RNA (mRNA) from these cells. In contrast, sequence analysis of the CD3ζ gene in DNA from the patient's T cells with normal levels of the T-cell receptor–CD3 complex showed that four sequences of the same mutated codon were present (Figure 3B). One of these sequences matched the mutated TAG sequence in the Q70X mutation, whereas the other three, which were present in equal proportions in total DNA from T cells with normal levels of the T-cell receptor–CD3 complex, had TGG, TTG, or TAT sequences at codon 70 (Figure 3B). These sequences were not detected in DNA and RNA from the patient's fibroblasts, B cells, or T cells with low levels of the T-cell receptor–CD3 complex, or in DNA from more than 100 chromosomes from control subjects. Because the patient's T cells with normal levels of the T-cell receptor–CD3 complex were not of maternal origin, the TGG, TTG, and TAT variants must have arisen by somatic mutation of one of the germ-line Q70X alleles. As a result, the patient's subgroup of T cells with normal levels of the T-cell receptor–CD3 complex was a mixture of cells, each of which contained the inherited Q70X mutation on one allele and one of the three somatic mutations on the other allele. These somatic mutations would lead to full-length variants carrying a tryptophan (W), a leucine (L), or a tyrosine (Y) at position 70 (Q70W, Q70L, or Q70Y, respectively), which is consistent with our finding of a CD3ζ chain that is close to its usual molecular weight at the plasma membrane in T cells with normal levels of the T-cell receptor–CD3 complex (Figure 3B).
Discussion
We describe a boy with greatly increased susceptibility to bacterial, viral, and fungal infections and a new type of T-cell immunodeficiency that was caused by a homozygous mutation (Q70X) of CD3ζ. This subunit of the T-cell receptor–CD3 complex is essential for the expression of the complex and its signaling function. The mutant Q70X gene impaired formation of the complex on the plasma membrane and thus rendered the affected T cells incapable of activation through the antigen receptor. The impaired activation of T cells was probably related to a truncated CD3ζ chain that was devoid of intracellular ITAM domains. These domains are necessary for the recruitment of the tyrosine kinase ZAP-70, which becomes activated by phosphorylation after recruitment to the complex. Phosphorylation of ZAP-70 allows signal transduction that culminates in T-cell activation. In 90 percent of the patient's T cells, the truncated CD3ζ chain was detected in small amounts in the cytoplasm but not on the membrane. Defective membrane expression of the T-cell receptor–CD3 complex may result from instability of CD3ζ mRNA, from the production of an unstable truncated protein, or from the role of the cytoplasmic tail of CD3ζ in the expression and signaling function of T-cell receptor–CD3 complexes on the plasma membrane.23 T-cell receptor–CD3 complexes lacking CD3ζ have been shown to be shunted from the Golgi complex to the lysosomal pathway for degradation,2 and in CD3ζ-deficient mice, the expression of these complexes is profoundly impaired.5-8 These mice also display a profound but incomplete block of T-cell development in the thymus,5-8 and they have few CD4+ and CD8+ T cells in lymphoid organs.24 Although in our patient the number of CD4+ and CD8+ T cells with low levels of the T-cell receptor–CD3 complex increased over time, the murine and human phenotypes generated by CD3ζ deficiency appear to be similar with respect to peripheral T cells.
Other CD3 deficiencies variably affect the development and function of T cells. Null mutations of the CD3δ or CD3ε gene lead to a complete absence of T cells.13,14 CD3γ deficiency, however, causes a much milder immunodeficiency25 than our patient had. The mosaic of phenotypes associated with deficiencies in the CD3ε, CD3δ, CD3γ, or CD3ζ chain highlights the complexity of T-cell receptor–CD3 signaling patterns, which are poorly understood.
The germ-line mutation of CD3ζ in our patient was associated with three somatic CD3ζ mutations, all located at the mutated codon 70 of the CD3ζ gene in the population with normal levels of the T-cell receptor–CD3 complex, which were obtained from 10 percent of the patient's T cells. These mutations apparently reversed the effect of the Q70X mutation and allowed the production of full-length CD3ζ variants in T cells with normal levels of the T-cell receptor–CD3 complex. These variants stably bound to the other CD3 subunits, resulting in levels of T-cell receptor–CD3 complexes in the plasma membrane that were close to levels in normal T cells. The mechanism of the poor proliferation of the patient's T cells with normal levels of the T-cell receptor–CD3 complex, both in vitro and in vivo, is unclear. It could not have been due to interference by FcεRIγ chains, which were not found in T-cell receptor–CD3 complexes from the patient's T cells with normal levels of the T-cell receptor–CD3 complex. These T cells, which were CD4+, were not natural regulatory T cells,26 because they did not express Foxp3, a transcription factor required for the development and function of such T cells. The lack of phosphorylated ZAP-70 protein in the patient's T cells with normal levels of the T-cell receptor–CD3 complex indicated that the CD3ζ variants on the plasma membrane could not transduce an effective signal of T-cell activation. Possibly, mutations affecting the Q70 residue of the first ITAM motif of CD3ζ impair the signaling function of this molecule.
The finding of somatic mutations of a germ-line mutation of the CD3ζ gene recalls somatic mutations of germ-line mutations of the adenosine deaminase, interleukin-2 receptor γc, recombination-activating gene 1, the Wiskott–Aldrich syndrome protein, and nuclear factor-κB essential modulator (NEMO, or IKKγ) genes. These somatic changes caused the mutant gene to revert to a wild-type gene or to a sequence compatible with expression of the corresponding protein.27-35 The somatic mutations occurring in the initially mutated codon of the CD3ζ gene are probably not due to a mutational hot spot related to genomic instability, since these variants were not found in other cell types from our patient. The T cells with normal levels of the T-cell receptor–CD3 complex were polyclonal, and each of the three somatic variants of CD3ζ was found in different populations of T cells, each with a distinctive rearrangement of Vβ genes (data not shown). This result indicates that the somatic mutations in CD3ζ probably occurred before the VDJ recombination process in T-cell progenitors.
In summary, we describe a form of T-cell immunodeficiency related to a recessive mutation of the CD3ζ gene. This observation adds to the reported variability in deficiencies of the various CD3 subunits. The characterization of somatic mutations partially correcting the CD3ζ deficiency provides an example of the modulation of T-cell immunodeficiency by somatic mutations and of the selection of clones with such mutations.
Supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche contre le Cancer, Ligue Nationale contre le Cancer, and the Jeffrey Modell Foundation.
No potential conflict of interest relevant to this article was reported.
We are indebted to C. Harre, C. Jacques, and S. Lemaire for technical assistance.
Source Information
From INSERM Unité 768 (F.R.-L., V.M., F.S., A.F.); Faculté de Médecine (F.R.-L., V.M., F.S., A.F.) and Unité d'Immunologie Hématologie Pédiatrique (I.P., A.F.), Université de Paris René Descartes; Hôpital Necker (F.R.-L., V.M., F.S., A.F.); INSERM Unité 520 and Institut Curie (C.H.); and INSERM Unité 668 and Unité d'Immunité Anti-virale, Biothérapies et Vaccin, Institut Pasteur (A.L.) — all in Paris; and Département de Microbiologie et d'Immunologie, Centre Hospitalier Universitaire Sainte-Justine, Montreal (F.L.D.).
Address reprint requests to Dr. Rieux-Laucat at INSERM Unité 768, Hôpital Necker, 149, rue de Sèvres, 75015 Paris, France, or at rieux@necker.fr.
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