title: Sprouty-2 regulates HIV-specific T cell polyfunctionality.
abstract: The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our findings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Chiu
authors.forename: Liang
authors.initials: L
authors.lastname: Shan
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.forename: Carl
authors.initials: C
authors.lastname: Haupt
authors.forename: Catherine
authors.initials: C
authors.lastname: Bessell
authors.forename: David H
authors.initials: DH
authors.lastname: Canaday
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Ho
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.forename: Mathias
authors.initials: M
authors.lastname: Oelke
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.forename: Joel N
authors.initials: JN
authors.lastname: Blankson
authors.forename: Diane E
authors.initials: DE
authors.lastname: Griffin
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Schneck
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome; D015854:Up-Regulation; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus