Activation of primary T lymphocytes results in lysosome development and polarized granule exocytosis in CD4+ and CD8+ subsets, whereas expression of lytic molecules confers cytotoxicity to CD8+ T cells.
Lytic granule exocytosis is the major cytotoxic mechanism used by CD8(+) cytotoxic lymphocytes. CD8(+) T cells acquire this effector function in the process characterized by lysosomal biogenesis, induction of expression of cytolytic molecules, and their selective sorting into the lysosomal vesicles. However, temporal relation of these differentiation stages during T cell activation has not been defined precisely. Also, although CD4(+) T cells typically do not express lytic molecules as a consequence of activation, and therefore, do not acquire granule exocytosis-mediated lytic function, it is not clear whether CD4(+) T cells are able to degranulate. By using in vitro TCR stimulation of primary mouse lymphocytes, we found that polyclonally activated CD4(+) T cells degranulate upon TCR ligation and polarize enlarged lysosomal granules in response to target cell recognition, despite the lack of granule exocytosis-mediated cytotoxicity. Upon TCR stimulation, resting CD8(+) T cells rapidly express lytic molecules and acquire potent lytic function early in activation. Maximal cytolytic potential, however, depends on enlargement of lysosomal granules during the subsequent activation stages. Thus, polyclonal TCR stimulation of resting T cells results in development of lysosomal granules and their release upon TCR engagement in CD4(+) and CD8(+) T cells, but only CD8(+) T cells acquire lytic function as a result of induction of expression of lytic molecules.
Shen
David T
DT
Children's National Medical Center, Center for Cancer and Immunology, Children's Research Institute, Washington, D.C. 20010, USA.
Ma
Jennifer S Y
JS
Mather
Jacques
J
Vukmanovic
Stanislav
S
Radoja
Sasa
S
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016764:Cell Polarity / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D005089:Exocytosis / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D008247:Lysosomes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D054353:Perforin; D053804:Granzymes