title: Selective expansion of memory CD4(+) T cells by mitogenic human CD28 generates inflammatory cytokines and regulatory T cells.
abstract: Costimulatory signals are important for development of effector and regulatory T cells. In this case, CD28 signaling is usually considered inert in the absence of signaling through the TCR. By contrast, mitogenic rat CD28 mAb reportedly expand regulatory T cells without TCR stimulation. We found that a commercially available human CD28 mAb (ANC28) stimulated PBMC without TCR co-ligation or cross-linking; ANC28 selectively expanded CD4(+)CD25(+)FOXP3(-) (Teff) and CD4(+)CD25(+)FOXP3(+) (Treg) cells. ANC28 stimulated the CD45RO(+) CD4(+) (memory) population, whereas CD45RA(+)CD4(+) (naive) cells did not respond. ANC28 also induced inflammatory cytokines. Treg induced by ANC28 retain the Treg phenotype longer than costimulated Treg. Treg induced by ANC28 suppressed CD25(-) T cells through a contact-dependent mechanism. Purity influenced the response of CD4(+)CD25(+ )cells because bead-purified CD4(+)CD25(+ )cells (85-90% pure) responded strongly to ANC28, whereas 98% pure FACS-sorted CD4(+)CD25(bright) (Treg) did not respond. Purified CD4(+)CD25(int) cells responded similarly to the bead-purified CD4(+)CD25(+) cells. Thus, pre-activated CD4(+) T cells (CD25(int)) respond to ANC28 rather than Treg (CD25(bright)). The ability of ANC28 to expand both effectors producing inflammatory cytokines as well as suppressive regulatory T cells might be useful for ex vivo expansion of therapeutic T cells.
authors.affiliation: Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA. ms12@bcm.edu
authors.forename: Manisha
authors.initials: M
authors.lastname: Singh
authors.forename: Sreemanti
authors.initials: S
authors.lastname: Basu
authors.forename: Christina
authors.initials: C
authors.lastname: Camell
authors.forename: Jacob
authors.initials: J
authors.lastname: Couturier
authors.forename: Rodolfo J
authors.initials: RJ
authors.lastname: Nudelman
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Medina
authors.forename: John R
authors.initials: JR
authors.lastname: Rodgers
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007140:Immunoglobulin Fab Fragments; D053645:Interleukin-2 Receptor alpha Subunit; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017493:Leukocyte Common Antigens; D000077191:Wortmannin