title: Regulatory and conventional CD4+ T cells show differential effects correlating with PD-1 and B7-H1 expression after immunotherapy.
abstract: Recently, our laboratory reported that secondary CD8+ T cell-mediated antitumor responses were impaired following successful initial antitumor responses using various immunotherapeutic approaches. Although immunotherapy stimulated significant increases in CD8+ T cell numbers, the number of CD4+ T cells remained unchanged. The current investigation revealed a marked differential expansion of CD4+ T cell subsets. Successful immunotherapy surprisingly resulted in an expansion of CD4+Foxp3+ regulatory T (Treg) cells concurrent with a reduction of conventional CD4+ T (Tconv) cells, despite the marked antitumor responses. Following immunotherapy, we observed differential up-regulation of PD-1 on the surface of CD4+Foxp3+ Treg cells and CD4+Foxp3- Tconv cells. Interestingly, it was the ligand for PD-1, B7-H1 (PDL-1), that correlated with Tconv cell loss after treatment. Furthermore, IFN-gamma knockout (IFN-gamma-/-) and IFN-gamma receptor knockout (IFN-gammaR-/-) animals lost up-regulation of surface B7-H1 even though PD-1 expression of Tconv cells was not changed, and this correlated with CD4+ Tconv cell increases. These results suggest that subset-specific expansion may contribute to marked shifts in the composition of the T cell compartment, potentially influencing the effectiveness of some immunotherapeutic approaches that rely on IFN-gamma.
authors.affiliation: Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.
authors.forename: Kory L
authors.initials: KL
authors.lastname: Alderson
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Vanessa
authors.initials: V
authors.lastname: Berner
authors.forename: Danice E C
authors.initials: DE
authors.lastname: Wilkins
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Welniak
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Doug
authors.initials: D
authors.lastname: Redelman
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000954:Antigens, Surface / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000096:biosynthesis*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D019013:CD40 Antigens; C498919:Cd274 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins