Reduced T-cell receptor CD3zeta-chain protein and sustained CD3epsilon expression at the site of mycobacterial infection.
Control of mycobacterial infection by the cellular immune system relies both on antigen-presenting cells and on T lymphocytes. The quality of an effective cellular immune response is dependent on functional signal transduction residing in the cytoplasmic tails of the T-cell receptor CD3 components. In order to investigate potential effects of mycobacteria on T-cell receptor signalling, we examined the protein expression of T-cell signal transduction molecules (CD3zeta, ZAP-70, p59fyn, p56lck). In Western blots of peripheral blood mononuclear cells of Mycobacterium tuberculosis infected patients, only the CD3zeta-chain showed a marked reduction in protein expression. To investigate the situation in situ, immunoenzymatic and immunofluorescence stainings for CD3epsilon and CD3zeta expression were performed on sections of normal lymphoid tissue, M. leprae infected and sarcoid tissue. CD3epsilon and CD3zeta expression were similar with respect to intensity, localization and the number of cells stained in normal lymphoid tissue and in sarcoid granulomas. In contrast, the granulomas of M. leprae infected tissues showed a significantly reduced expression of CD3zeta compared to CD3epsilon. Using double immunofluorescence analysis, virtually no CD3zeta expression could be detected in comparison to the CD3epsilon expression in the lesions. Apparently, mycobacteria are capable of significantly reducing CD3zeta-chain expression, which may be restored by cytokines. IL-2-enhanced zeta-chain expression and T-cell effector functions, defined by interferon-gamma release, in M. tuberculosis-specific and human leucocyte antigen-DR restricted CD4+ T cells isolated from granuloma lesions from patients with pulmonary tuberculosis. Because CD3zeta is essential for CD3 signalling and for eliciting T-cell effector functions, reduced CD3zeta protein expression could result in altered signal transduction and inefficient T-cell effector functions. Alternatively, reduced CD3zeta-chain expression may protect T cells from repetitive TCR stimulation associated with anergy or apoptosis.
Seitzer
U
U
Division of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany. useitzer@fz-borstel.de
Kayser
K
K
Höhn
H
H
Entzian
P
P
Wacker
H H
HH
Ploetz
S
S
Flad
H D
HD
Gerdes
J
J
Maeurer
M J
MJ
D017252:CD3 Complex; D005455:Fluorescent Antibody Technique; D006099:Granuloma / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D007376:Interleukin-2 / Q000276:immunology; D015440:Leprosy, Lepromatous / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism*; D009164:Mycobacterium Infections / Q000276:immunology*; D014066:Palatine Tonsil / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000097:blood; D011518:Proto-Oncogene Proteins / Q000097:blood; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017565:Sarcoidosis, Pulmonary / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase
D017252:CD3 Complex; C115335:CD3E protein, human; D007376:Interleukin-2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human