Marcos Timón

Primary Immunodeficiency Caused by Mutations in the Gene Encoding the CD3-γ Subunit of the T-Lymphocyte Receptor

PRIMARY immunodeficiency diseases are a heterogeneous group of disorders resulting from intrinsic defects of the immune system.1 They are frequently associated with repeated bacterial, fungal, or v...

Herpes virus saimiri transformation of T cells in CD3γ immunodeficiency: phenotypic and functional characterization

The characterization of T cell immunodeficiencies could in part be supported by using stable cell lines in which biochemical and molecular studies of the defect could be carried out thereby omitting frequent bleeding of patients. First attempts to obtain such cell lines included HTLV-I transformation and exogenous IL-2 administration, but both models have important disadvantages. Recently, a virus isolated from the squirrel monkey, Herpes virus saimiri (HVS), has been reported to have the ability to transform T cells. A stable IL-2-dependent HVS-transformed T cell line from a CD3 gamma deficient patient has been obtained; and this cell line displays both the phenotypic and the functional characteristics of the patients lymphocytes. Moreover, the line down-modulates TCR/CD3 surface expression upon CD3 engagement, as do the patients lymphocytes, showing that CD3 gamma and its phosphorylation are not necessary for TCR/CD3 internalization. In addition, the abnormal staining pattern of different anti-TCR/CD3 monoclonal antibodies is preserved in the HVS-patient line. Since HVS is capable of transforming CD3 gamma- T cells, the CD3 gamma chain does not seem to be involved in the HVS receptor process. The fact that it is not possible to obtain a CD8+ HVS line from the CD3 gamma- patient supports the existence of a functional anomaly in his scanty CD8+ peripheral lymphocytes. Thus, HVS transformation is a suitable model for T cell immunodeficiency studies and characterization. It may also be used in the future in cellular models for in vitro gene therapy trials.

Primary T lymphocyte immunodeficiency associated with a selective impairment of CD2, CD3, CD43 (but not CD28)-mediated signal transduction

A 2‐year‐old female with important signs of immune response failure against virus, bacteria, fungi and protozoa and no obvious humoral or lymphocyte phenotypical defect was studied. Both peripheral blood mononuclear cells and IL‐2‐dependent T cell lines derived from the patient showed a severe selective T cell activation impairment via CD2, CD3 and CD43; however, this defect was reversible with the addition of either IL‐2, or phorbol myristate acetate (PMA) or anti‐CD28 antibodies, Concordantly, the induction of IL‐2 (and, in part, IL‐3 and IL‐4) messenger RNA Vk‐as severely reduced in stimulated T cells, but that of other cytokines was either normal (IL‐5) or only slightly diminished (interferon‐gamma (IFN–γ)). It is concluded that an activation T cell defect exists previous to protein kinase C (PKC) and between membrane receptors and the activation pathway of certain response genes encoding for interleukins involved in proliferation (i.e. lL‐2, IL‐3 and IL‐4), but not of others (i.e. IL‐5). The use of T ceil lines from human T lymphocyte activation deficiencies allows dissection of T cell pathology and the corresponding physiological pathways. In the present description, there is an evident independence of the CD28 T cell activation pathway from those induced through CD2 or CD3, and the differential gene regulation of the different interleukins.

From Pathology to Physiology of the Human T‐Lymphocyte Receptor

The recent description of a selective human CD3γ deficiency and other T‐cell receptor (TCR)/CD3 structural and functional defects, together with previous biochemical data on the structure and interactions of the TCR/CD3 complex, may aid in elucidating the physiology of this multi‐subunit membrane ensemble. CD3γ seemed to be required for the commitment and thymic maturation of an important fraction of T lymphocytes to the CD8 (but not CD4) lineage, perhaps by participating with the CD8 co‐receptor in the instructive signal delivered throtigh the αβ TCR during intrathymic positive selection by HLA class I molecules. The homologous CD3δ component would, in contrast, be necessary for the selection of CD4 lymphocytes by HLA class II molecules. The interaction of CD4 and CD8 with the TCR/CD3 complex during antigen recognition may thus be asymmetrical, taking place through CD3δ and γ respectively. Also, the existence of in vivo functional TCR/CD3 hemireceptors (lacking either CD3γ or CD3δ is suggested, and defects in their relative amount on the T‐cell surface may disrupt unresponsiveness to self antigens and generate autoimmunity.

A diallelic RFLP of the CD3-epsilon chain of the clonotypic T-lymphocyte receptor is not associated with certain autoimmune diseases

SummaryA diallelic restriction fragment length polymorphism of the CD3-epsilon (ɛ) gene, which encodes for an invariant component of the human T-lymphocyte receptor, is observed when using genomic DNA TaqI digests probed with a CD3-ɛ chain cDNA probe. This combination shows two alleles of 9.1 kb and 8.4 kb with a frequency of 0.66 and 0.34, respectively, in the Spanish population. None of these alleles is associated with susceptibility to juvenile rheumatoid arthritis (JRA) or insulin-dependent diabetes mellitus (IDDM).