title: IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3-dependent manner in human CD8(+) T cells.
abstract: Although both MHC class II/CD8α double-knockout and CD8β null mice show a defect in the development of MHC class I-restricted CD8(+) T cells in the thymus, they possess low numbers of high-avidity peripheral CTL with limited clonality and are able to contain acute and chronic infections. These in vivo data suggest that the CD8 coreceptor is not absolutely necessary for the generation of Ag-specific CTL. Lack of CD8 association causes partial TCR signaling because of the absence of CD8/Lck recruitment to the proximity of the MHC/TCR complex, resulting in suboptimal MAPK activation. Therefore, there should exist a signaling mechanism that can supplement partial TCR activation caused by the lack of CD8 association. In this human study, we have shown that CD8-independent stimulation of Ag-specific CTL previously primed in the presence of CD8 coligation, either in vivo or in vitro, induced severely impaired in vitro proliferation. When naive CD8(+) T cells were primed in the absence of CD8 binding and subsequently restimulated in the presence of CD8 coligation, the proliferation of Ag-specific CTL was also severely hampered. However, when CD8-independent T cell priming and restimulation were supplemented with IL-21, Ag-specific CD8(+) CTL expanded in two of six individuals tested. We found that IL-21 rescued partial MAPK activation in a STAT3- but not STAT1-dependent manner. These results suggest that CD8 coligation is critical for the expansion of postthymic peripheral Ag-specific CTL in humans. However, STAT3-mediated IL-21 signaling can supplement partial TCR signaling caused by the lack of CD8 association.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Osamu
authors.initials: O
authors.lastname: Imataki
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.forename: Makito
authors.initials: M
authors.lastname: Tanaka
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milstein
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D016827:CD8 Antigens; D007378:Interleukins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020928:Mitogen-Activated Protein Kinases; D000098546:Interleukin-21