title: A role for the thermal environment in defining co-stimulation requirements for CD4(+) T cell activation.
abstract: Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4+ T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4+ T cells to become more quickly and easily activated during times of infection during fever.
authors.affiliation: a Department of Cell Stress Biology ; Roswell Park Cancer Institute ; Buffalo , NY USA.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Zynda
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.forename: Lingwen
authors.initials: L
authors.lastname: Zhong
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.forename: Maegan
authors.initials: M
authors.lastname: Capitano
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ostberg
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
authors.forename: Arnd
authors.initials: A
authors.lastname: Pralle
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005454:Fluorescence Polarization; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013049:Spectrin / Q000378:metabolism; D013696:Temperature; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D017487:Ankyrins; D018106:CD28 Antigens; D007376:Interleukin-2; D012333:RNA, Messenger; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D013049:Spectrin; D013755:Tetradecanoylphorbol Acetate
keywords: APC, antigen-presenting cell; CD28, cluster of differentiation 28; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CTxB, cholera toxin B subunit; Ct, cycle threshold; ELISA, enzyme-linked immunosorbant assay; EtOH, ethanol; FITC, fluoroisothiocyanate; GM1, monosialotetrahexosylganglioside; IDEAS, imagestream data exploration and analysis software; IL-2, interleukin 2; LA, latrunculin A; MβCD, methyl-β-cyclodextrin; PD-1, Programmed cell death-1; PMA, phorbol 12-myristate 13-acetate; T cell activation; T cell co-stimulation; TCR, T cell receptor; TDI, time delay integration; TMA-DPH, trimethylammonium diphenylhexatriene; WBH, whole body hyperthermia.; fever; hyperthermia; immune response; membrane fluidity; pMHC, peptide-major histocompatibility complexes; qRT-PCR, quantitative reverse transcription polymerase chain reaction