title: Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4+ T cells.
abstract: Costimulatory molecules of the CD28 family on T lymphocytes integrate cues from innate immune system sensors and modulate activation responses in conventional CD4(+) T cells (Tconv) and their FoxP3(+) regulatory counterparts (Treg). To better understand how costimulatory and coinhibitory signals might be integrated, we profiled the changes in gene expression elicited in the hours and days after engagement of Treg and Tconv by anti-CD3 and either anti-CD28, -CTLA4, -ICOS, -PD1, -BLA, or -CD80. In Tconv, a shared "main response" was induced by CD28, ICOS, and, surprisingly, BTLA and CD80, with very limited CD28-specific (primarily Il2) or ICOS-specific elements (including Th1 and Th2 but not the follicular T signature). CTLA4 and PD1 had a very subtle impact in this system, similarly inhibiting the response to anti-CD3. Treg responded to the same costimulatory hierarchy and to the same extent as Tconv, but inducing different clusters of genes. In this reductionist system, costimulatory or coinhibitory engagement mainly elicits generic responses, suggesting that the variability of their effects in vivo result from temporal or anatomical differences in their engagement, rather than from inherently different wiring.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ei
authors.initials: E
authors.lastname: Wakamatsu
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000235:genetics; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; C488868:BTLA protein, mouse; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic