title: NKG2D signaling on CD8⁺ T cells represses T-bet and rescues CD4-unhelped CD8⁺ T cell memory recall but not effector responses.
abstract: CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8(+) T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8(+) T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4(+) T cells in a CD4-dependent influenza model and rescues HIV-specific CD8(+) T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8(+) T cells from their pathophysiological fate and may provide therapeutic benefits.
authors.affiliation: Department of Surgery, Committee on Immunology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Lyons
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schenkel
authors.forename: Tamson V
authors.initials: TV
authors.lastname: Moore
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lacek
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: O'Sullivan
authors.forename: Vineeth
authors.initials: V
authors.lastname: Varanasi
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jagoda
authors.forename: Emily C
authors.initials: EC
authors.lastname: Bellavance
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Marzo
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Biljana
authors.initials: B
authors.lastname: Zafirova
authors.forename: Bojan
authors.initials: B
authors.lastname: Polić
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D007376:Interleukin-2; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D019444:Vaccines, DNA; D007371:Interferon-gamma