title: Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells.
abstract: Some human memory CD4(+) T cells have cytotoxic functions best understood in the context of viral infections; however, their possible role in pathologic processes is understudied. The novel discovery that mitogenic CD28 antibodies induced proliferation and expansion of Tregs offered therapeutic promise for autoimmune disorders. However, the failed TGN1412 trial forced reassessment of this concept. As memory CD4(+) T cells are known to produce toxic molecules, including granzyme B (GrzB) and FasL, we wondered whether mitogenic CD28 was able to induce these cytotoxic molecules. A commercially available mitogenic human CD28 mAb (clone ANC28.1) was used to determine whether mitogenic CD28 induces cytotoxic function from human memory CD4(+) T cells. We found that stimulation of memory CD4(+) T cells by ANC28.1, as well as by conventional costimulation (CD3/CD28 mAb), robustly induced enzymatically active GrzB, along with increased surface expression of FasL. These functional phenotypes were induced in association with increased expression of T cell activation markers CD69 and CD25, and elimination of target cells by ANC28.1-activated memory CD4(+) T cells involved both GrzB and FasL. Additionally, ANC28.1-activated memory CD4(+) T cells caused disruption of epithelial cell monolayer integrity, which was partially mediated by GrzB. These findings reveal functions of memory CD4(+) T cells previously unknown to be induced by mitogenic CD28, and suggest that these pathogenic mechanisms may have been responsible for some of the widespread tissue destruction that occurred in the TGN1412 trial recipients.
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Medina
authors.forename: Jacob
authors.initials: J
authors.lastname: Couturier
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Feske
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Mahne
authors.forename: Mary
authors.initials: M
authors.lastname: Turner
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yu
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Kozinetz
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Orozco
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Hutchison
authors.forename: Tor C
authors.initials: TC
authors.lastname: Savidge
authors.forename: John R
authors.initials: JR
authors.lastname: Rodgers
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism*; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008934:Mitogens / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D053222:Fas Ligand Protein; D008934:Mitogens; D053804:Granzymes