Differential expression and function of α-mannosidase I in stimulated naive and memory CD4+ T cells

• Published in: Journal of immunotherapy (1997) Vol. 34; no. 5; p. 428
• Main Authors: Gebuhr, Inga, Keeren, Kathrin, Vogt, Katrin, Höflich, Conny, Appelt, Christine, Schlieer, Ulrike, Brandt, Christine, Meisel, Christian, Volk, Hans-Dieter, Sawitzki, Birgit
• Format: Journal Article
• Language: English
• Published: United States 01.06.2011
• Subjects: Alkaloids - pharmacology; alpha-Mannosidase - antagonists & inhibitors; alpha-Mannosidase - genetics; alpha-Mannosidase - immunology; alpha-Mannosidase - metabolism; Animals; Antibodies - immunology; Antibodies - pharmacology; Antigens, CD - analysis; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Enzyme Inhibitors - pharmacology; Gene Silencing; Humans; Immunologic Memory; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Retroviridae; RNA, Small Interfering - pharmacology; Transcription, Genetic - drug effects; Transfection
• ISSN: 1537-4513
• DOI: 10.1097/CJI.0b013e31821dcf23

N-linked protein glycosylation represents an important cellular process for modifying protein properties. It resembles a cascade of various enzymatic reactions, in which class I α-mannosidases play a central role. We and others have recently shown that N-glycosylation plays a major role for immune functions. We now analyzed the expression and function of α-mannosidase I in CD4(+) naive and memory T cells studying human and murine T cells. Alpha-mannosidase I function was altered by (i) treatment with Kifunensine, a specific inhibitor class I α-mannosidases, (ii) synthetic inhibitory RNA, and (iii) overexpression by retroviral gene transfer. T-cell activation was evaluated by CD69 expression, cytokine production and proliferation. Our results demonstrate (i) that α-mannosidase I transcription is transiently downregulated after T-cell activation with either polyclonal anti-CD3/CD28 antibodies or allogeneic CD19(+) B cells, and (ii) that α-mannosidase I exerts an inhibitory effect on T-cell activation. It is interesting to note that the inhibitory effect was restricted to naive CD4(+) T cells in both systems, human T cells and murine transgenic CD4(+)OT-II cells, whereas human memory T cells and primed CD4(+)OT-II cells remained unaffected. Alpha-mannosidase I inhibition reduced the activation threshold for naive but not already primed CD4(+)OT-II cells as the cells were able to respond to lower ovalbumin peptide concentrations and increased the rejection potential of alloreactive T cells in vivo. Thus, complex N-glycans generated by enzymes such as α-mannosidase I inhibit the activation of naive T cells. These findings could be used to improve the ex vivo priming of naive T cells for adaptive T-cell therapies.