title: TCR stimulation without co-stimulatory signals induces expression of "tolerogenic" genes in memory CD4 T cells but does not compromise cell proliferation.
abstract: Memory T cells resist co-stimulatory blockade and present a unique therapeutic challenge in transplantation and autoimmune diseases. Herein, we determined whether memory T cells express less "tolerogenic" genes than naïve T cells to reinforce a proliferative response under the deprivation of co-stimulatory signals. The expression of ∼40 tolerogenic genes in memory and naïve CD4(+) T cells was thus assessed during an in vitro TCR stimulation without co-stimulation. Briefly, upon TCR stimulation with an anti-CD3 mAb alone, memory CD4(+) T cells exhibited more proliferation than naïve CD4(+) T cells. To our surprise, at 24h upon anti-CD3 mAb stimulation, memory CD4(+) T cells expressed more than a 5-fold higher level of the transcription factor Egr2 and a 20-fold higher level of the transmembrane E3 ubiquitin ligase GRAIL than those in naïve T cells. Hence, the high-level expression of tolerogenic genes, Egr2 and GRAIL, in memory CD4(+) T cells does not prevent cell proliferation. Importantly, anti-CD3 mAb-stimulated memory CD4(+) T cells expressed high protein/gene levels of phosphorylated STAT5, Nedd4, Bcl-2, and Bcl-XL. Therefore, co-stimulation-independent proliferation of memory CD4(+) T cells may be due to elevated expression of molecules that support cell proliferation and survival, but not lack of tolerogenic molecules.
authors.affiliation: Center for Immunobiology and Transplantation Research, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, United States; Department of Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Aini
authors.initials: A
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Luwan Branch, Shanghai 200020, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo OH 43614, United States.
authors.forename: Mithun
authors.initials: M
authors.lastname: Khattar
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo OH 43614, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Schroder
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo OH 43614, United States. Electronic address: Stanislaw.Stepkowski@utoledo.edu.
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Stepkowski
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address: jiahong.xia@mail.hust.edu.cn.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
authors.affiliation: Center for Immunobiology and Transplantation Research, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, United States; Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo OH 43614, United States.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics*; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C513258:Prdm1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: Co-stimulation; Gene expression; Memory T cells; Tolerogenic